Pyridine compounds

ABSTRACT

The present invention relates to a compound or a pharmacologically acceptable salt thereof having excellent tissue non-specific alkaline phosphatase inhibitory activity. The present invention provides a compound represented by the formula (I): wherein R 1  represents a hydrogen atom, an optionally substituted C1-6 alkyl group, or the like, R 2  and R 3  are the same or different and each represent a hydrogen atom, an optionally substituted C1-6 alkyl group, or the like, R4 and R5 are the same or different and each represent a hydrogen atom, an optionally substituted C1-6 alkyl group, or the like, R 6  represents a hydrogen atom or the like, each R 7  may be the same or different and may each represent an optionally substituted C1-6 alkoxy group or the like, X represents —CH═, —C(—R 7 )═, or —N═, and m represents 1 to 4, or a pharmacologically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.62/190,145, filed Jul. 8, 2015, expressly incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a novel pyridine compound or apharmacologically acceptable salt thereof which has excellent tissuenon-specific alkaline phosphatase (hereinafter, referred to as TNAP)inhibitory activity.

The present invention also relates to a therapeutic agent and/orprophylactic agent (preferably a therapeutic agent) for pseudoxanthomaelasticum (PXE), generalized arterial calcification of infancy (GACI),craniometaphyseal dysplasia (CMD), ossification of the yellow ligament(OYL), ossification of ligamentum flavum, arterial calcification due todeficiency of CD73 (ACDC), calcification of joints and arteries (CALJA),arthrosis deformans, osteoarthritis, ankylosis of the joint, idiopathicinfantile arterial calcification (IIAC), ankylosing spondylitis (AS),tumoral calcinosis (TC), progressive osseous heteroplasia (POH), Keutelsyndrome, vascular calcification associated with chronic renal failure(including glomerulonephritis, IgA nephropathy, hypertensivenephropathy, and diabetic nephropathy) and secondary parathyroidhyperplasia, metastatic calcification, calciphylaxis, calcifictendinitis of the longus colli muscle, fibrodysplasia ossificansprogressiva (FOP), calcific aortic stenosis, pericarditis calculosa,atherosclerotic vascular calcification, calcific uremic arteriopathy(CUA), Kawasaki disease, calcification due to obesity and aging, tibialarterial calcification, bone metastasis, prosthetic calcification,Paget's disease, idiopathic basal ganglia calcification (IBGC),heterotopic ossification (HO), calcific aortic valve disease (aorticvalve stenosis), calcific tendinitis, ossification of the posteriorlongitudinal ligament (OPLL) ossification of the anterior longitudinalligament (OALL), diffuse idiopathic skeletal hyperostosis (DISH),meniscal calcification, or peritoneal calcification, comprising thecompound or the pharmacologically acceptable salt thereof as an activeingredient.

The present invention further relates to a composition for the treatmentor prophylaxis of the aforementioned diseases, comprising the compoundor the pharmacologically acceptable salt thereof as an activeingredient, use of the compound or the pharmacologically acceptable saltthereof for manufacturing a pharmaceutical for the treatment orprophylaxis of the disease, and a method for the treatment orprophylaxis of the disease, comprising administering a pharmacologicallyeffective amount of the compound or the pharmacologically acceptablesalt thereof to a mammal (preferably a human).

DESCRIPTION OF THE RELATED ART

In vivo calcification is strictly regulated by the balance of activationbetween osteoblasts and osteoclasts, phosphorus and calciumconcentrations in plasma, and parathyroid hormone or vitamin D secretedin order to maintain the homeostasis of these concentrations (Non PatentLiterature 1). Ectopic calcification is found in diseases, for example,pseudoxanthoma elasticum (PXE), generalized arterial calcification ofinfancy (GACI), craniometaphyseal dysplasia (CMD), ossification of theyellow ligament (OYL), ossification of ligamentum flavum, arterialcalcification due to deficiency of CD73 (ACDC), calcification of jointsand arteries (CALJA), arthrosis deformans, osteoarthritis, ankylosis ofthe joint, idiopathic infantile arterial calcification (IIAC),ankylosing spondylitis (AS), tumoral calcinosis (TC), progressiveosseous heteroplasia (POH), Keutel syndrome, vascular calcificationassociated with chronic renal failure (including glomerulonephritis, IgAnephropathy, hypertensive nephropathy, and diabetic nephropathy) andsecondary parathyroid hyperplasia, metastatic calcification,calciphylaxis, calcific tendinitis of the longus colli muscle,fibrodysplasia ossificans progressiva (FOP), calcific aortic stenosis,pericarditis calculosa, atherosclerotic vascular calcification, calcificuremic arteriopathy (CUA), Kawasaki disease, calcification due toobesity and aging, tibial arterial calcification, bone metastasis,prosthetic calcification, Paget's disease, idiopathic basal gangliacalcification (IBGC), heterotopic ossification (HO), calcific aorticvalve disease (aortic valve stenosis), calcific tendinitis, ossificationof the posterior longitudinal ligament (OPLL) ossification of theanterior longitudinal ligament (OALL), diffuse idiopathic skeletalhyperostosis (DISH), meniscal calcification, and peritonealcalcification. In these pathological conditions, calcification intissues (blood vessels, soft tissues, etc.) that are usually notcalcified is caused by the failure of the regulatory mechanism mentionedabove, and is known to bring about significantly reduced quality of life(QOL) due to the limitation of activity and an increased cardiovascularrisk (Non Patent Literatures 2 and 3). No existing therapeutic agent iseffective for ectopic calcification. Thus, there are very high unmetmedical needs for this disease (Non Patent Literature 4).

TNAP, one of alkaline phosphatases, includes membrane-bound andsecretory forms. TNAP is expressed in the bone, the liver, and thekidney and highly expressed particularly in the matrix vesicles ofchondrocytes and osteoblasts. This enzyme is known to play an importantrole in in vivo calcification via the degradation of pyrophosphate,which is an endogenous anti-calcification factor (Non Patent Literature5). A large number of reports show the increased expression level orelevated activity of TNAP at lesion sites of ectopic calcification, andectopic calcification also occurs in mice which overexpress human TNAP,suggesting the importance of TNAP for ectopic calcification (Non PatentLiteratures 6 and 7). Thus, the inhibition of TNAP is considered toelevate pyrophosphate concentrations in blood and in tissues andsuppress ectopic calcification (Non Patent Literature 8).

Some compounds are known to have TNAP inhibitory activity (see e.g.,Patent Literatures 1 and 2 and, Non Patent Literatures 9 to 12). Amongthem, compounds partially having a common skeleton are disclosed.Nonetheless, a compound having a 7-membered ring condensed with apyridine ring has not yet been disclosed.

PATENT LITERATURE

-   [Patent Literature 1] International Publication No. WO 2009/017863    (PCT/US2008/063106)-   [Patent Literature 2] International Publication No. WO 2013/126608    (U.S. Patent Publication No. 2015-0011551)

Non Patent Literature

-   [Non Patent Literature 1] J. Bone Miner Res, 2006, vol. 24, p.    176-181-   [Non Patent Literature 2] Clin. Kidery. J., 2014, vol. 7, p. 167-173-   [Non Patent Literature 3] Eur. Heart. J., 2014, vol. 35, p.    1515-1525.-   [Non Patent Literature 4] Int. J. Nephrol. Renovasc. Dis., 2014,    vol. 7, p. 161-168-   [Non Patent Literature 5] J. Histochem. Cytochem., 2002, vol. 50, p.    333-340-   [Non Patent Literature 6] J. Am. Soc. Nephrol., 2004, vol. 15, p.    1392-1401-   [Non Patent Literature 7] J. Bone Miner Res, 2013, vol. 7, p.    1587-1598-   [Non Patent Literature 8] J. Bone Miner Res, 2007, vol. 22, p.    1700-1710-   [Non Patent Literature 9] Bioorg. Med. Chem. Lett., 2009, vol.    19, p. 222-225-   [Non Patent Literature 10] J. Med. Chem., 2009, vol. 52, p.    6919-6925-   [Non Patent Literature 11] Bioorg. Med. Chem., 2013, vol. 21, p.    7981-7897-   [Non Patent Literature 12] J. Bone Miner Res, 2015, vol. 30, p.    824-836

SUMMARY OF THE INVENTION

The present inventors have conducted diligent studies and consequentlyfound that a compound represented by the formula (I) mentioned later hasexcellent TNAP inhibitory activity based on its specific chemicalstructure, further has excellent properties in terms of thephysicochemical properties (e.g., stability) of a pharmaceutical, andserves as a safe and useful pharmaceutical as a prophylactic ortherapeutic agent for a pathological condition or a disease associatedwith ectopic calcification. On the basis of these findings, the presentinvention has been completed.

Specifically, the compound of the present invention has excellentproperties in terms of TNAP inhibitory activity, solubility, cellmembrane permeability, oral absorbability, concentration in blood,metabolic stability, tissue penetration, bioavailability (hereinafter,also referred to as BA), in vitro activity, in vivo activity, ex vivoactivity, quick onset of drug efficacy, persistence of drug efficacy,physical stability, drug interaction, safety (e.g., cardiotoxicity orhepatotoxicity), etc., and is useful as a pharmaceutical [particularly,a pharmaceutical for the treatment or prophylaxis (preferably treatment)of pseudoxanthoma elasticum (PXE), generalized arterial calcification ofinfancy (GACI), craniometaphyseal dysplasia (CMD), ossification of theyellow ligament (OYL), ossification of ligamentum flavum, arterialcalcification due to deficiency of CD73 (ACDC), calcification of jointsand arteries (CALJA), arthrosis deformans, osteoarthritis, ankylosis ofthe joint, idiopathic infantile arterial calcification (IIAC),ankylosing spondylitis (AS), tumoral calcinosis (TC), progressiveosseous heteroplasia (POH), Keutel syndrome, vascular calcificationassociated with chronic renal failure (including glomerulonephritis, IgAnephropathy, hypertensive nephropathy, and diabetic nephropathy) andsecondary parathyroid hyperplasia, metastatic calcification,calciphylaxis, calcific tendinitis of the longus colli muscle,fibrodysplasia ossificans progressiva (FOP), calcific aortic stenosis,pericarditis calculosa, atherosclerotic vascular calcification, calcificuremic arteriopathy (CUA), Kawasaki disease, calcification due toobesity and aging, tibial arterial calcification, bone metastasis,prosthetic calcification, Paget's disease, idiopathic basal gangliacalcification (IBGC), heterotopic ossification (HO), calcific aorticvalve disease (aortic valve stenosis), calcific tendinitis, ossificationof the posterior longitudinal ligament (OPLL) ossification of theanterior longitudinal ligament (OALL), diffuse idiopathic skeletalhyperostosis (DISH), meniscal calcification, or peritonealcalcification].

The present invention provides:

(1) a compound represented by the following general formula (I):

wherein

R¹ represents

a hydrogen atom,

a C1-6 alkyl group (wherein the alkyl group is optionally substituted byone to three groups, which may be the same or different, selected fromthe following substituents:

a hydroxy group, a C1-6 alkoxy group optionally substituted by one tothree groups, which may be the same or different halogeno groups, anamino group optionally substituted by one or two groups, which may bethe same or different C1-6 alkyl groups, a C6-10 aryl group optionallysubstituted by one or two groups selected from substituent group A^(B),a 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur and optionally substituted by one or two groupsselected from substituent group A^(B), a carboxyl group, a C1-6alkylcarbonyl group, a C1-6 alkoxycarbonyl group, an aminocarbonyl groupoptionally substituted by one or two groups, which may be the same ordifferent C1-6 alkyl groups, a 4- to 7-membered saturatedheterocyclylcarbonyl group containing one or two heteroatoms, which maybe the same or different, selected from nitrogen, oxygen, and sulfur, anaminocarbonyloxy group optionally substituted by one or two groups,which may be the same or different C1-6 alkyl groups, a 4- to 7-memberedsaturated heterocyclylcarbonyloxy group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur),a C3-8 cycloalkyl group (wherein the cycloalkyl group is optionallysubstituted by one to three groups, which may be the same or different,selected from the following substituents:a hydroxy group, a C1-6 alkoxy group optionally substituted by one tothree groups, which may be the same or different halogeno groups, a C3-8cycloalkyl group optionally substituted by one to three groups, whichmay be the same or different halogeno groups, a C6-10 aryl groupoptionally substituted by one or two groups, which may be the same ordifferent halogeno groups, a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur and optionally substituted byone or two groups, which may be the same or different halogeno groups,a carboxyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonylgroup, an aminocarbonyl group optionally substituted by one or twogroups, which may be the same or different C1-6 alkyl groups, a 4- to7-membered saturated heterocyclylcarbonyl group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur, an aminocarbonyloxy group optionally substituted byone or two groups, which may be the same or different C1-6 alkyl groups,a 4- to 7-membered saturated heterocyclylcarbonyloxy group containingone or two heteroatoms, which may be the same or different, selectedfrom nitrogen, oxygen, and sulfur,a halogeno group, and a cyano group),a C6-10 aryl group (wherein the aryl group is optionally substituted byone or two groups, which may be the same or different, selected from thefollowing substituents:a hydroxy group, a C1-6 alkyl group optionally substituted by one tothree groups, which may be the same or different halogeno groups, a C3-8cycloalkyl group optionally substituted by one to three groups, whichmay be the same or different halogeno groups, a C1-6 alkoxy groupoptionally substituted by one to three groups, which may be the same ordifferent halogeno groups,a C6-10 aryl group optionally substituted by one group selected fromsubstituent group A^(B), a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur and optionally substituted byone group selected from substituent group A^(B),a carboxyl group, an amino group optionally substituted by one or twogroups, which may be the same or different C1-6 alkyl groups,a C1-6 alkoxycarbonyl group,an aminocarbonyl group optionally substituted by one or two groups,which may be the same or different C1-6 alkyl groups, a 4- to 7-memberedsaturated heterocyclylcarbonyl group containing one or two heteroatoms,which may be the same or different, selected from nitrogen, oxygen, andsulfur, an aminocarbonyloxy group optionally substituted by one or twogroups, which may be the same or different C1-6 alkyl groups, a 4- to7-membered saturated heterocyclylcarbonyloxy group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur,a halogeno group, and a cyano group), ora 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur (wherein the heterocyclyl group is optionallysubstituted by one or two groups, which may be the same or different,selected from the following substituents:a hydroxy group, a C1-6 alkyl group optionally substituted by one tothree groups, which may be the same or different halogeno groups, a C3-8cycloalkyl group optionally substituted by one to three groups, whichmay be the same or different halogeno groups, a C1-6 alkoxy groupoptionally substituted by one to three groups, which may be the same ordifferent halogeno groups,a C6-10 aryl group, a 3- to 10-membered heterocyclyl group containingone to four heteroatoms, which may be the same or different, selectedfrom nitrogen, oxygen, and sulfur, a carboxyl group, an amino group,an aminocarbonyl group optionally substituted by one or two groups,which may be the same or different C1-6 alkyl groups, a 4- to 7-memberedsaturated heterocyclylcarbonyl group containing one or two heteroatoms,which may be the same or different, selected from nitrogen, oxygen, andsulfur, an aminocarbonyloxy group optionally substituted by one or twogroups, which may be the same or different C1-6 alkyl groups, a 4- to7-membered saturated heterocyclylcarbonyloxy group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur,a halogeno group, and a cyano group),

R² and R³ are the same or different and each represent

a hydrogen atom,

a C1-6 alkyl group (wherein the alkyl group is optionally substituted byone to three groups, which may be the same or different, selected fromthe following substituents:

a hydroxy group, a C1-6 alkoxy group optionally substituted by one groupselected from substituent group A^(C),

a C3-8 cycloalkyl group optionally substituted by one group selectedfrom substituent group A^(B), a C6-10 aryl group optionally substitutedby one or two groups selected from substituent group A^(B), a 3- to10-membered heterocyclyl group containing one to four heteroatoms, whichmay be the same or different, selected from nitrogen, oxygen, and sulfurand optionally substituted by one or two groups selected fromsubstituent group A^(B),a carboxyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonylgroup, an amino group optionally substituted by one or two groups, whichmay be the same or different C1-6 alkyl groups,an aminocarbonyl group optionally substituted by one or two groups,which may be the same or different C1-6 alkyl groups, a 4- to 7-memberedsaturated heterocyclylcarbonyl group containing one or two heteroatoms,which may be the same or different, selected from nitrogen, oxygen, andsulfur, an aminocarbonyloxy group optionally substituted by one or twogroups, which may be the same or different C1-6 alkyl groups, a 4- to7-membered saturated heterocyclylcarbonyloxy group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur,a halogeno group, and a cyano group),a C6-10 aryl group (wherein the aryl group is optionally substituted byone or two groups, which may be the same or different, selected from thefollowing substituents:a hydroxy group, a C1-6 alkoxy group optionally substituted by one tothree groups, which may be the same or different halogeno groups,a C1-6 alkyl group optionally substituted by one group selected fromsubstituent group A^(D), a C3-8 cycloalkyl group optionally substitutedby one group selected from substituent group A^(D), a C6-10 aryl groupoptionally substituted by one group selected from substituent groupA^(D), a 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur and optionally substituted by one group selected fromsubstituent group A^(D),an amino group optionally substituted by one or two groups, which may bethe same or different C1-6 alkyl groups,a carboxyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonylgroup, an aminocarbonyl group optionally substituted by one or twogroups, which may be the same or different C1-6 alkyl groups, a 4- to7-membered saturated heterocyclylcarbonyl group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur, an aminocarbonyloxy group optionally substituted byone or two groups, which may be the same or different C1-6 alkyl groups,a 4- to 7-membered saturated heterocyclylcarbonyloxy group containingone or two heteroatoms, which may be the same or different, selectedfrom nitrogen, oxygen, and sulfur,a halogeno group, and a cyano group),a 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur (wherein the heterocyclyl group is optionallysubstituted by one or two groups, which may be the same or different,selected from the following substituents:a hydroxy group, a C1-6 alkoxy group optionally substituted by one tothree groups, which may be the same or different halogeno groups,a C1-6 alkyl group optionally substituted by one group selected fromsubstituent group A^(D), a C3-8 cycloalkyl group optionally substitutedby one group selected from substituent group A^(D), a C6-10 aryl groupoptionally substituted by one group selected from substituent groupA^(D), a 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur and optionally substituted by one group selected fromsubstituent group A^(D),an amino group optionally substituted by one or two groups, which may bethe same or different C1-6 alkyl groups,a carboxyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonylgroup, an aminocarbonyl group optionally substituted by one or twogroups, which may be the same or different C1-6 alkyl groups, a 4- to7-membered saturated heterocyclylcarbonyl group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur, an aminocarbonyloxy group optionally substituted byone or two groups, which may be the same or different C1-6 alkyl groups,a 4- to 7-membered saturated heterocyclylcarbonyloxy group containingone or two heteroatoms, which may be the same or different, selectedfrom nitrogen, oxygen, and sulfur,a halogeno group, and a cyano group),a C1-6 alkylcarbonyl group (wherein the alkylcarbonyl group isoptionally substituted by one to three groups, which may be the same ordifferent, selected from substituent group A^(E)),a C6-10 arylcarbonyl group (wherein the arylcarbonyl group is optionallysubstituted by one or two groups, which may be the same or different,selected from substituent group A^(E) and a C1-6 halogenoalkyl group),a 3- to 10-membered heterocyclylcarbonyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur (wherein the heterocyclylcarbonyl group is optionallysubstituted by one or two groups, which may be the same or different,selected from substituent group A^(E) and a C1-6 halogenoalkyl group),a carboxyl group,a C1-6 alkoxycarbonyl group (wherein the alkoxycarbonyl group isoptionally substituted by one to three groups, which may be the same ordifferent, selected from substituent group A^(F)),an aminocarbonyl group (wherein the aminocarbonyl group is optionallysubstituted by one or two groups, which may be the same or differentC1-6 alkyl groups each optionally substituted by one to three groups,which may be the same or different, selected from substituent groupA^(F)),a C6-10 arylaminocarbonyl group (wherein the arylaminocarbonyl group isoptionally substituted by one or two groups, which may be the same ordifferent, selected from substituent group A^(E) and a C1-6halogenoalkyl group),a 4- to 7-membered saturated heterocyclylcarbonyl group containing oneor two heteroatoms, which may be the same or different, selected fromnitrogen, oxygen, and sulfur (wherein the heterocyclylcarbonyl group isoptionally substituted by one to three groups, which may be the same ordifferent, selected from substituent group A^(F)), ora 3- to 10-membered heterocyclylaminocarbonyl group containing one tofour heteroatoms, which may be the same or different, selected fromnitrogen, oxygen, and sulfur (wherein the heterocyclylaminocarbonylgroup is optionally substituted by one or two groups, which may be thesame or different, selected from substituent group A^(E) and a C1-6halogenoalkyl group),or

the C1-6 alkyl groups of R² and R³ are optionally bonded to each otherto form a 3- to 6-membered saturated carbocyclic ring or to form a 4- to6-membered saturated heterocyclic ring via one nitrogen or oxygen atom(wherein one nitrogen atom in the 4- to 6-membered saturatedheterocyclic ring is optionally replaced with a hydrogen atom, a C1-6alkyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonyl group),

R⁴ and R⁵ are the same or different and each represent

a hydrogen atom,

a C1-6 alkyl group (wherein the alkyl group is optionally substituted byone to three groups, which may be the same or different, selected fromsubstituent group A^(G)),

a C6-10 aryl group (wherein the aryl group is optionally substituted byone or two groups, which may be the same or different, selected fromsubstituent group A^(G)), or

a 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur (wherein the heterocyclyl group is optionallysubstituted by one or two groups, which may be the same or different,selected from substituent group A^(G)),R⁶ represents a hydrogen atom, hydroxyl group or a C1-6 alkyl group (R⁶is a carbon substituent of the pyridinyl ring, not a nitrogensubstituent),

each substituent R⁷ may be the same or different and may each represent

a C1-6 alkyl group (wherein the alkyl group is optionally substituted byone to three groups, which may be the same or different, selected fromsubstituent group A^(H)),

a C1-6 alkoxy group (wherein the alkoxy group is optionally substitutedby one to three groups, which may be the same or different, selectedfrom substituent group A^(H)),

a halogeno group,

a C6-10 aryl group (wherein the aryl group is optionally substituted byone or two groups, which may be the same or different, selected fromsubstituent group A^(G)),

a 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur (wherein the heterocyclyl group is optionallysubstituted by one or two groups, which may be the same or different,selected from substituent group A^(G)),a hydroxy group,an amino group (wherein the amino group is optionally substituted by oneor two groups, which may be the same or different C1-6 alkyl groups eachoptionally substituted by one to three groups, which may be the same ordifferent, selected from substituent group A^(J)),a carboxyl group,a C1-6 alkoxycarbonyl group (wherein the alkoxycarbonyl group isoptionally substituted by one to three groups, which may be the same ordifferent, selected from substituent group A^(J)),an aminocarbonyl group (wherein the aminocarbonyl group is optionallysubstituted by one or two groups, which may be the same or differentC1-6 alkyl groups each optionally substituted by one to three groups,which may be the same or different, selected from substituent groupA^(J)), ora cyano group,

X represents —CH═, —C(—R⁷)═, or —N═,

m represents an integer selected from 1 to 4, and

the substituent groups represent

A^(B): a hydroxy group, a C1-6 alkyl group (wherein the alkyl group isoptionally substituted by one to three halogeno groups), a C1-6 alkoxygroup (wherein the alkoxy group is optionally substituted by one tothree halogeno groups), a halogeno group, an amino group, and a cyanogroup;A^(C): a C6-10 aryl group, a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur, and a halogeno group;A^(D): a hydroxy group, a C1-6 alkoxy group, an amino group, a halogenogroup, and a cyano group;A^(E): a hydroxy group, a C1-6 alkoxy group, a C3-8 cycloalkyl group, aC6-10 aryl group, a 3- to 10-membered heterocyclyl group containing oneto four heteroatoms, which may be the same or different, selected fromnitrogen, oxygen, and sulfur, an amino group (wherein the amino group isoptionally substituted by one or two groups, which may be the same ordifferent C1-6 alkyl groups), a halogeno group, and a cyano group;A^(F): a C1-6 alkoxy group, a C3-8 cycloalkyl group, a C6-10 aryl group,a 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur, a halogeno group, and a cyano group;A^(G): a hydroxy group, a C1-6 alkoxy group, an amino group (wherein theamino group is optionally substituted by one or two groups, which may bethe same or different C1-6 alkyl groups), a halogeno group, and a cyanogroup;A^(H): a hydroxy group, a C1-6 alkoxy group, a C3-8 cycloalkyl group, aC6-10 aryl group, a 3- to 10-membered heterocyclyl group containing oneto four heteroatoms, which may be the same or different, selected fromnitrogen, oxygen, and sulfur, a carboxyl group, a C1-6 alkoxycarbonylgroup, an aminocarbonyl group (wherein the aminocarbonyl group isoptionally substituted by one or two groups, which may be the same ordifferent C1-6 alkyl groups), an amino group (wherein the amino group isoptionally substituted by one or two groups, which may be the same ordifferent C1-6 alkyl groups), a halogeno group, and a cyano group; andA^(J): a C1-6 alkoxy group, a C3-8 cycloalkyl group, a C6-10 aryl group,a 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur, a carboxyl group, a C1-6 alkoxycarbonyl group, anaminocarbonyl group (wherein the aminocarbonyl group is optionallysubstituted by one or two groups, which may be the same or differentC1-6 alkyl groups), a halogeno group, and a cyano group,or a pharmacologically acceptable salt thereof;(2) a compound represented by the following general formula (Ia):

wherein

R¹ represents a hydrogen atom, a C1-6 alkyl group (wherein the alkylgroup is optionally substituted by one hydroxy group or C1-6 alkoxygroup), a C6-10 aryl group, or a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur,

R² and R³ are the same or different and each represent a hydrogen atomor a C1-6 alkyl group (wherein the alkyl group is optionally substitutedby one hydroxy group), or

the C1-6 alkyl groups of R² and R³ are optionally bonded to each otherto form a 3- to 6-membered saturated carbocyclic ring,

each substituent R⁷ may be the same or different and may represent aC1-6 alkoxy group (wherein the alkoxy group is optionally substituted byone to three halogeno groups) or a halogeno group,

X represents —CH═, —C(—R⁷)═, or —N═, and

m represents an integer of 1 or 2,

or a pharmacologically acceptable salt thereof;

(3) a compound according to the above (2), wherein R¹ is hydrogen atom;

(4) a compound according to the above (2), wherein R² and R³ are thesame or different and each represent a hydrogen atom or the C1-6 alkylgroups of R² and R³ are optionally bonded to each other to form a 3- to6-membered saturated carbocyclic ring;

(5) a compound according to the above (2), wherein each substituent R⁷may be the same or different and may represent a methoxy group, ethoxygroup, trifluoromethoxy group, fluoro or chloro;

(6) a compound according to the above (1) selected from the groupconsisting of:

-   5-chloro-2-methoxy-N-(4-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide;-   5-fluoro-2-methoxy-N-(4-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide;-   5-chloro-N-[4-(2-hydroxyethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide;-   5-fluoro-2-methoxy-N-[(3S)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide;-   5-chloro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide;-   5-fluoro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide;-   5-bromo-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide;-   5-chloro-N-[(3S)-3-(2-hydroxyethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide;    and-   pharmacologically acceptable salts thereof;    (7) a compound according to the above (1) selected from the group    consisting of:-   5-chloro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide;-   5-chloro-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-(trifluoromethoxy)benzenesulfonamide;-   5-chloro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-(trifluoromethoxy)benzenesulfonamide;-   5-fluoro-2-methoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide;-   5-chloro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)-2-(trifluoromethoxy)benzenesulfonamide;-   5-fluoro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)-2-(trifluoromethoxy)benzenesulfonamide;-   2,5-dimethoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide;    and-   pharmacologically acceptable salts thereof;    (8) a compound according to the above (1), where the compound is    5-fluoro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide,    or a pharmacologically acceptable salt thereof;    (9) a compound according to the above (1), where the compound is    5-chloro-2-methoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide,    or a pharmacologically acceptable salt thereof;    (10) a compound according to the above (1), where the compound is-   2-ethoxy-5-fluoro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide,    or a pharmacologically acceptable salt thereof;    (11) a compound according to the above (1) to (10), wherein the    pharmacologically acceptable salt is sodium salt;    (12) a compound according to the above (1) to (10), wherein the    pharmacologically acceptable salt is potassium salt;    (13) a pharmaceutical composition comprising a compound according to    the above (1) to (10) or a pharmacologically acceptable salt thereof    as an active ingredient;    (14) the pharmaceutical composition according to the above (13),    wherein the pharmaceutical composition is intended for the treatment    or prophylaxis of ectopic calcification, pseudoxanthoma elasticum    (PXE), generalized arterial calcification of infancy (GACI),    calcification of joints and arteries (CALJA), vascular calcification    in CKD/ESRD, calciphylaxis, ossification of posterior longitudinal    ligaments (OPLL), ossification of yellow ligaments (OYLL), or aortic    stenosis;    (15) a TNAP inhibitor comprising a compound according to the    above (1) to (10) or a pharmacologically acceptable salt thereof as    an active ingredient;    (16) a method for the treatment or prophylaxis of a disease or    condition selected from the group consisting of ectopic    calcification, pseudoxanthoma elasticum (PXE), generalized arterial    calcification of infancy (GACI), calcification of joints and    arteries (CALJA), vascular calcification in CKD/ESRD, calciphylaxis,    ossification of posterior longitudinal ligaments (OPLL),    ossification of yellow ligaments (OYLL), and aortic stenosis,    comprising administering a therapeutically effective amount of a    compound according to the above (1) to (10) or a pharmacologically    acceptable salt thereof to a subject in need thereof;    (17) a method according to (16), wherein the disease or condition is    pseudoxanthoma elasticum (PXE);    (18) a method for inhibiting TNAP in a subject, comprising    administering an effective amount of a compound according to the    above (1) to (10) or a pharmacologically acceptable salt thereof to    the subject;    (19) a method according to the above (16) to (18), wherein the    subject is a human;    (20) use of a compound according to the above (1) to (10) or a    pharmacologically acceptable salt thereof for the manufacturing a    pharmaceutical composition;    (21) a compound according to the above (1) to (10) or a    pharmacologically acceptable salt thereof for use in the treatment    of disease or condition selected from the group consisting of    ectopic calcification, pseudoxanthoma elasticum (PXE), generalized    arterial calcification of infancy (GACI), calcification of joints    and arteries (CALJA), vascular calcification in CKD/ESRD,    calciphylaxis, ossification of posterior longitudinal ligaments    (OPLL), ossification of yellow ligaments (OYLL), and aortic    stenosis; and    (22) a compound according to the above (1) to (10) or a    pharmacologically acceptable salt thereof for use in the treatment    of pseudoxanthoma elastic (PXE).

In the present invention, the “C1-6 alkyl group” refers to a linear orbranched alkyl group having 1 to 6 carbon atoms. Examples thereof caninclude methyl, ethyl, n-propyl, n-butyl, isobutyl, s-butyl, tert-butyl,n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl,isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and2-ethylbutyl groups. For R¹, R², R³, R⁴, R⁵, R⁶, R⁷, or A^(B), the C1-6alkyl group is preferably an alkyl group having 1 to 3 carbon atoms,most preferably an ethyl or methyl group.

In the present invention, the “C1-6 alkylcarbonyl group” refers to theaforementioned “C1-6 alkyl group” bonded to a carbonyl group. Examplesthereof can include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,n-butylcarbonyl, isobutylcarbonyl, s-butylcarbonyl, tert-butylcarbonyl,n-pentylcarbonyl, isopentylcarbonyl, 2-methylbutylcarbonyl,neopentylcarbonyl, 1-ethylpropylcarbonyl, n-hexylcarbonyl,isohexylcarbonyl, 4-methylpentylcarbonyl, 3-methylpentylcarbonyl,2-methylpentylcarbonyl, 1-methylpentylcarbonyl,3,3-dimethylbutylcarbonyl, 2,2-dimethylbutylcarbonyl,1,1-dimethylbutylcarbonyl, 1,2-dimethylbutylcarbonyl,1,3-dimethylbutylcarbonyl, 2,3-dimethylbutylcarbonyl, and2-ethylbutylcarbonyl groups. For R¹, R², or R³, the C1-6 alkylcarbonylgroup is preferably an alkylcarbonyl group having 1 to 3 carbon atoms,most preferably a methylcarbonyl group.

In the present invention, the “C3-8 cycloalkyl group” refers to a 3- to8-membered saturated cyclic hydrocarbon group. Examples thereof caninclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl groups. For R¹, R², R³, R⁴, R⁵, R⁷, A^(E), A^(F), A^(H),or A^(J), the C3-8 cycloalkyl group is preferably a 3- to 6-memberedsaturated cyclic hydrocarbon group, more preferably a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl group.

In the present invention, the “C6-10 aryl group” refers to an aromatichydrocarbon group having 6 to 10 carbon atoms. Examples thereof caninclude phenyl, indenyl, and naphthyl groups. For R¹, R², R³, R⁴, R⁵,R⁷, A^(C), A^(E), A^(F), A^(H), or A^(J), the C6-10 aryl group ispreferably a phenyl group.

In the present invention, the “C1-6 alkoxy group” refers to theaforementioned “C1-6 alkyl group” bonded to an oxygen atom. Examplesthereof can include linear or branched alkoxy groups each having 1 to 6carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy,neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy,2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, and2,3-dimethylbutoxy. For R¹, R², R³, R⁷, A^(B), A^(D), A^(E), A^(F),A^(G), A^(H), or A^(J), the C1-6 alkoxy group is preferably a methoxy orethoxy group.

In the present invention, the “C1-6 alkoxycarbonyl group” refers to theaforementioned “C1-6 alkoxy group” bonded to a carbonyl group. Examplesthereof can include linear or branched alkoxycarbonyl groups each having1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, s-butoxycarbonyl, tert-butoxycarbonyl,n-pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl,neopentoxycarbonyl, n-hexyloxycarbonyl, 4-methylpentoxycarbonyl,3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl,3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl,1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl,1,3-dimethylbutoxycarbonyl, and 2,3-dimethylbutoxycarbonyl. For R¹, R²,R³, R⁷, A^(H), or A^(J), the C1-6 alkoxycarbonyl group is preferably amethoxycarbonyl or ethoxycarbonyl group.

In the present invention, the “4- to 7-membered saturated heterocyclylgroup containing one or two heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur” refers to a 4- to7-membered saturated heterocyclic group containing one or two atoms ofnitrogen, oxygen, and sulfur. Examples thereof can include oxetanyl,morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl,tetrahydrofuranyl, tetrahydropyranyl, and5-oxo-4,5-dihydro-1,2,4-oxadiazolyl groups.

In the present invention, the “4- to 7-membered saturatedheterocyclylcarbonyl group containing one or two heteroatoms, which maybe the same or different, selected from nitrogen, oxygen, and sulfur”refers to the aforementioned “4- to 7-membered saturated heterocyclylgroup containing one or two heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur” bonded to acarbonyl group. Examples thereof can include morpholinylcarbonyl,thiomorpholinylcarbonyl, pyrrolidinylcarbonyl, pyrrolinylcarbonyl,piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl,tetrahydropyranylcarbonyl, and5-oxo-4,5-dihydro-1,2,4-oxadiazolylcarbonyl groups.

In the present invention, the “4- to 7-membered saturatedheterocyclylcarbonyloxy group containing one or two heteroatoms, whichmay be the same or different, selected from nitrogen, oxygen, andsulfur” refers to the aforementioned “4- to 7-membered saturatedheterocyclylcarbonyl group containing one or two heteroatoms, which maybe the same or different, selected from nitrogen, oxygen, and sulfur”bonded to an oxygen atom. Examples thereof can includemorpholinylcarbonyloxy, thiomorpholinylcarbonyloxy,pyrrolidinylcarbonyloxy, pyrrolinylcarbonyloxy, piperidinylcarbonyloxy,piperazinylcarbonyloxy, tetrahydrofuranylcarbonyloxy,tetrahydropyranylcarbonyloxy, and5-oxo-4,5-dihydro-1,2,4-oxadiazolylcarbonyloxy groups.

In the present invention, the “3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur” refers to a 3- to10-membered heterocyclic group containing one to four atoms of nitrogen,oxygen, and sulfur. Examples thereof can include the groups listed asthe examples of the aforementioned “4- to 7-membered heterocyclyl groupcontaining one or two heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur”, and aromatic heterocyclicgroups such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl,imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl,pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. The “3- to 10-memberedheterocyclic group” may be condensed with an additional cyclic group.Examples thereof can include benzofuranyl, chromenyl, indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl,quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,isoindolinyl, 2,3-dihydro-1-benzofuranyl, 3,4-dihydro-1H-isochromenyl,1,2,3,4-tetrahydroquinolinyl, and 1,2,3,4-tetrahydroisoquinolinylgroups.

In the present invention, the “3- to 10-membered heterocyclylcarbonylgroup containing one to four heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur” refers to theaforementioned “3- to 10-membered heterocyclyl group containing one tofour heteroatoms, which may be the same or different, selected fromnitrogen, oxygen, and sulfur” bonded to a carbonyl group. Examplesthereof can include the groups listed as the examples of theaforementioned “4- to 7-membered saturated heterocyclylcarbonyl groupcontaining one or two heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur”, and carbonyl groups ofaromatic heterocyclic groups such as furylcarbonyl, thienylcarbonyl,pyrrolylcarbonyl, azepinylcarbonyl, pyrazolylcarbonyl,imidazolylcarbonyl, oxazolylcarbonyl, oxadiazolylcarbonyl,isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl,1,2,3-oxadiazolylcarbonyl, triazolylcarbonyl, tetrazolylcarbonyl,thiadiazolylcarbonyl, pyranylcarbonyl, pyridylcarbonyl,pyridazinylcarbonyl, pyrimidinylcarbonyl, and pyrazinylcarbonyl groups.

In the present invention, the “3- to 10-memberedheterocyclylaminocarbonyl group containing one or two heteroatoms, whichmay be the same or different, selected from nitrogen, oxygen, andsulfur” refers to the aforementioned “3- to 10-membered heterocyclylgroup containing one to four heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur” bonded to acarbonyl group via an amino group. Examples thereof can includeaminocarbonyl groups of aromatic heterocyclic groups such asfurylaminocarbonyl, thienylaminocarbonyl, pyrrolylaminocarbonyl,azepinylaminocarbonyl, pyrazolylaminocarbonyl, imidazolylaminocarbonyl,oxazolylaminocarbonyl, oxadiazolylaminocarbonyl,isoxazolylaminocarbonyl, thiazolylaminocarbonyl,isothiazolylaminocarbonyl, 1,2,3-oxadiazolylaminocarbonyl,triazolylaminocarbonyl, tetrazolylaminocarbonyl,thiadiazolylaminocarbonyl, pyranylaminocarbonyl, pyridylaminocarbonyl,pyridazinylaminocarbonyl, pyrimidinylaminocarbonyl, andpyrazinylaminocarbonyl groups.

In the present invention, the “halogeno group” refers to a fluoro,chloro, bromo, or iodo group. For R¹, R², R³, R⁷, A^(B), A^(C), A^(D),A^(E), A^(F), A^(G), A^(H), or A^(J), the halogeno group is preferably afluoro, chloro, or bromo group.

Preferably, R¹ of the present invention is a hydrogen atom, a C1-6 alkylgroup (wherein the alkyl group is optionally substituted by one hydroxygroup or C1-6 alkoxy group), a C6-10 aryl group, or a 3- to 10-memberedheterocyclyl group containing one to four heteroatoms, which may be thesame or different, selected from nitrogen, oxygen, and sulfur.

Preferably, R² and R³ of the present invention are the same or differentand each represent a hydrogen atom or a C1-6 alkyl group (wherein thealkyl group is optionally substituted by one hydroxy group), or the C1-6alkyl groups of R² and R³ are bonded to each other to form a 3- to6-membered saturated carbocyclic ring.

Preferably, each of R⁴ and R⁵ of the present invention is a hydrogenatom.

Preferably, R⁶ of the present invention is a hydrogen atom.

Preferably, each R⁷ of the present invention, which may be the same ordifferent, represents a C1-6 alkoxy group (wherein the alkoxy group isoptionally substituted by one to three halogeno groups) or a halogenogroup.

The compound represented by the general formula (I) of the presentinvention can form a salt with a base. Such a salt with a base isincluded in the scope of the present invention. Examples of the saltwith a base can include: alkali metal salts such as lithium salt, sodiumsalt, potassium salt, and cesium salt; alkaline earth metal salts suchas magnesium salt, calcium salt, and barium salt; inorganic nitrogencompound salts such as ammonium salt and hydrazine salt; primary aminesalts such as methylamine salt, ethylamine salt, n-propylamine salt,isopropylamine salt, n-butylamine salt, 2-butylamine salt, isobutylaminesalt, and tert-butylamine salt; secondary amine salts such asdimethylamine salt, diethylamine salt, diisopropylamine salt,pyrrolidine salt, piperidine salt, and morpholine salt; tertiary aminesalts such as triethylamine salt and N-methylmorpholine salt; andaromatic amine salts such as pyridine salt,4-(N,N-dimethylamino)pyridine salt, imidazole salt, and1-methylimidazole salt. The salt is preferably an alkali metal salt,most preferably sodium salt or potassium salt. The compound representedby the general formula (I) of the present invention can form any ratioof a salt with a base. The respective salts with bases or mixturesthereof are included in the scope of the present invention.

The compound represented by the general formula (I) of the presentinvention can form an acid-addition salt, depending on its substituent.Such an acid-addition salt is included in the scope of the presentinvention. The compound represented by the general formula (I) of thepresent invention can form any ratio of an acid-addition salt, dependingon its substituent. The respective acid-addition salts (e.g., monoacidsalt and hemi-acid salt) or mixtures thereof are included in the salt ofthe present invention.

The compound represented by the general formula (I) of the presentinvention or the pharmacologically acceptable salt thereof can form ananhydrate, a hydrate, or a solvate. The respective forms or mixturesthereof are included in the scope of the present invention.

When the compound represented by the general formula (I) of the presentinvention or the pharmacologically acceptable salt thereof has at leastone asymmetric center, carbon-carbon double bond, axial chirality,tautomerism, or the like, optical isomers (including enantiomers anddiastereomers), geometric isomers, rotational isomers, and tautomers mayexist. These isomers and mixtures thereof are represented by a singleformula such as the formula (I). The present invention encompasses theseisomers and mixtures (including racemates) thereof at any ratio.

The compound represented by the general formula (I) of the presentinvention or the pharmacologically acceptable salt thereof can form anisotopic compound by the replacement of one or more atoms constitutingthe compound or the salt with isotopes at nonnatural ratios. Theisotopes can be radioactive or nonradioactive. Examples thereof includedeuterium (²H; D), tritium (³H; T), carbon-14 (¹⁴C), and iodine-125(¹²⁵I). The radioactive or nonradioactive isotopic compound may be usedas a pharmaceutical for the treatment or prophylaxis of a disease, areagent for research (e.g., a reagent for assay), a diagnostic agent(e.g., a diagnostic imaging agent), or the like. The present inventionencompasses these radioactive or nonradioactive isotopic compounds.

The compound represented by the general formula (I) of the presentinvention can be produced by, for example, the following method:

Method A:

In the structural formulas of the compounds in the method A and thedescription below, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, m, and X are as definedin the formula (I);

L¹ represents a nitro group, a halogeno group, or an amino group and ispreferably a nitro group or a bromo group; and

L² represents a halogeno group and is preferably a chloro group.

When a compound serving as a reactive substrate in the reaction of eachstep in the method A has a group inhibiting the reaction of interest,such as an amino group, a hydroxy group, or a carboxyl group, anappropriate protective group may be introduced to the functional groupand the introduced protective group may be removed, if necessary. Such aprotective group is not particularly limited as long as the protectivegroup is one usually used. The protective group can be a protectivegroup described in, for example, T. W. Greene, P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons,Inc. The reactions for the introduction and removal of these protectivegroups can be carried out according to routine methods such as methodsdescribed in the literature.

The solvent for use in the reaction of each step in the method A is notparticularly limited as long as the solvent partially dissolves startingmaterials without inhibiting the reaction. The solvent is selected from,for example, the following solvent group: aliphatic hydrocarbons such ashexane, pentane, heptane, petroleum ether, and cyclohexane; aromatichydrocarbons such as toluene, benzene, and xylene; halogenatedhydrocarbons such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene;ethers such as diethyl ether, diisopropyl ether, cyclopentylmethylether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane,dimethoxyethane, and diethylene glycol dimethyl ether; ketones such asacetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone;esters such as methyl acetate, ethyl acetate, propyl acetate, butylacetate, and diethyl carbonate; nitriles such as acetonitrile,propionitrile, butyronitrile, and isobutyronitrile; organic acids suchas formic acid, acetic acid, propionic acid, trifluoroacetic acid, andpentafluoropropionic acid; alcohols such as methanol, ethanol,1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and2-methyl-2-propanol; amides such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone, N,N′-dimethylpropyleneurea,and hexamethylphosphortriamide; sulfoxides such as dimethyl sulfoxideand sulfolane; water; and mixtures thereof.

The acid for use in the reaction of each step in the method A mentionedbelow is not particularly limited as long as the acid does not inhibitthe reaction. The acid is selected from the following acid group:inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, phosphoric acid, sulfuric acid, and nitric acid; organic acidssuch as formic acid, acetic acid, propionic acid, trifluoroacetic acid,and pentafluoropropionic acid; and organic sulfonic acids such asmethanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonicacid, and camphorsulfonic acid.

The base for use in the reaction of each step in the method A mentionedbelow is not particularly limited as long as the base does not inhibitthe reaction. The base is selected from the following base group: alkalimetal carbonates such as lithium carbonate, sodium carbonate, potassiumcarbonate, and cesium carbonate; alkali metal bicarbonates such aslithium bicarbonate, sodium bicarbonate, and potassium bicarbonate;alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, andpotassium hydroxide; alkaline earth metal hydroxides such as calciumhydroxide and barium hydroxide; alkali metal phosphates such as sodiumphosphate and potassium phosphate; alkali metal hydrides such as lithiumhydride, sodium hydride, and potassium hydride; alkali metal amides suchas lithium amide, sodium amide, and potassium amide; metal alkoxidessuch as lithium methoxide, sodium methoxide, sodium ethoxide, sodiumtert-butoxide, and potassium tert-butoxide; lithium amides such aslithium diisopropylamide (LDA), lithium cyclohexylisopropylamide, andlithium tetramethylpiperazide; alkali metal silylamides such as lithiumbistrimethylsilylamide, sodium bistrimethylsilylamide, and potassiumbistrimethylsilylamide; alkyllithiums such as methyllithium,n-butyllithium, sec-butyllithium, and tert-butyllithium; alkyl magnesiumhalides such as methyl magnesium chloride, methyl magnesium bromide,methyl magnesium iodide, ethyl magnesium chloride, ethyl magnesiumbromide, isopropyl magnesium chloride, isopropyl magnesium bromide, andisobutyl magnesium chloride; and organic amines such as triethylamine,tributylamine, diisopropylethylamine, diethylamine, diisopropylamine,N-methylpiperidine, N-methylmorpholine, N-ethylmorpholine, pyridine,picoline, 2,6-lutidine, 4-(N,N-dimethylamino)pyridine,N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane (DABCO),and 1,8-diazabicyclo[5,4,0]-7-undecene (DBU).

In the reaction of each step in the method A mentioned below, thereaction temperature differs depending on solvents, starting materials,reagents, etc., and the reaction time differs depending on solvents,starting materials, reagents, etc.

After the completion of the reaction of each step in the method Amentioned below, the compound of interest of each step is isolated fromthe reaction mixture according to a routine method. The compound ofinterest is obtained, for example, by: (i) if necessary, filtering offinsoluble matter such as a catalyst; (ii) adding water and awater-immiscible solvent (e.g., methylene chloride, chloroform, diethylether, ethyl acetate, or toluene) to the reaction mixture to extract thecompound of interest; (iii) washing the organic layer with water,followed by drying using a desiccant such as anhydrous sodium sulfate oranhydrous magnesium sulfate; and (iv) distilling off the solvent. Theobtained compound of interest can be further purified, if necessary, bya routine method, for example, recrystallization, reprecipitation, orsilica gel column chromatography. Alternatively, the compound ofinterest of each step may be used directly in the next reaction withoutbeing purified.

In the reaction of each step in the method A mentioned below, opticalisomers can be resolved by resolution using a chiral column.

Hereinafter, the reaction of each step in the method A will bedescribed.

(Step A-1)

Step A-1 is the step of condensing compound (1) with compound (2) toproduce compound (3). The compound (2) is known in the art or is easilyobtained from a compound known in the art.

The method for condensing a carboxylic acid with an amine differsdepending on the type of the carboxylic acid and can be generallycarried out by a method well known in the techniques of organicsynthetic chemistry, for example, a method described in ComprehensiveOrganic Transformations (Second Edition, 1999, John Wiley & Sons, Inc.,pp. 1929-1930, 1941-1949, and 1953-1954). A preferred method involvesconverting the carboxylic acid to a corresponding acid halide, which isthen condensed with a corresponding amine. Thus, step A-1 comprises:

(step A-1a): the step of reacting compound (1) with a halogenatingagent; and

(step A-1b): the step of reacting the compound obtained in the step A-1awith compound (2) in the presence of a base.

(Step A-1a)

Examples of the halogenating agent used can include: thionyl chloride,phosphorus trichloride, phosphorus oxychloride, phosphoruspentachloride, phosphorus tribromide, phosphorus pentabromide, oxalylchloride, carbon tetrachloride-triphenylphosphine,hexachloroethane-triphenylphosphine,N-chlorosuccinimide-triphenylphosphine, carbontetrabromide-triphenylphosphine, andN-bromosuccinimide-triphenylphosphine; and combinations of thesehalogenating agents with additives such as N,N-dimethylformamide. Thehalogenating agent is preferably a combination of thionyl chloride withan additive or a combination of oxalyl chloride with an additive, morepreferably a combination of oxalyl chloride with N,N-dimethylformamide.

Examples of the solvent used can include aliphatic hydrocarbons,aromatic hydrocarbons, halogenated hydrocarbons, ethers, and esters. Thesolvent is preferably a halogenated hydrocarbon or an ether, morepreferably methylene chloride or tetrahydrofuran.

The reaction temperature is preferably 0° C. to 100° C., more preferablyroom temperature.

The reaction time is preferably 15 minutes to 6 hours.

(Step A-1b)

Examples of the base used can include alkali metal carbonates, alkalimetal bicarbonates, alkali metal hydrides, lithium amides, alkali metalsilylamides, alkyllithiums, and organic amines. The base is preferablyan organic amine, more preferably triethylamine ordiisopropylethylamine.

Examples of the solvent used can include aliphatic hydrocarbons,aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, andamides. The solvent is preferably an ether or an amide, more preferablytetrahydrofuran or N,N-dimethylformamide.

The reaction temperature is preferably −78° C. to 100° C., morepreferably −20° C. to room temperature.

The reaction time is preferably 15 minutes to 24 hours.

(Step A-2)

Step A-2 is the step of intramolecularly cyclizing the compound (3)obtained in the step A-1b in the presence of a base to produce compound(4). The compound (4) of interest of this step can also be converted, ifnecessary, to another compound (4) of interest through deprotectionreaction. Alternatively, the compound (4) of interest of this step canalso be converted, if necessary, to another compound (4) of interestthrough modification reaction on the nitrogen atom of the amide group.

Examples of the base used can include alkali metal carbonates, alkalimetal bicarbonates, alkali metal hydrides, alkali metal hydroxides,alkaline earth metal hydroxides, alkali metal alkoxides, lithium amides,alkali metal silylamides, and organic amines. The base is preferably analkali metal hydride, an alkali metal carbonate, an alkali metalsilylamide, or an organic amine, more preferably sodiumbistrimethylsilylamide, sodium hydride, potassium carbonate, or cesiumcarbonate.

Examples of the solvent used can include aliphatic hydrocarbons,aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,esters, nitriles, ketones, and amides. The solvent is preferably anether, a nitrile, or an amide, more preferably tetrahydrofuran,acetonitrile, or N,N-dimethylformamide.

The reaction temperature is preferably −78° C. to 100° C.

The reaction time is preferably 15 minutes to 24 hours.

The reaction for converting the compound (4) of interest obtained inthis step to another compound (4) of interest by the removal of theprotective group differs depending on the type of the protective groupand can be generally carried out according to a routine method such as amethod well known in the techniques of organic synthetic chemistry, forexample, a method described in T. W. Greene, P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons,Inc.

The reaction for converting the compound (4) of interest obtained inthis step to another compound (4) of interest through modification onthe nitrogen atom of the amide group is not particularly limited as longas the reaction does not influence the other parts of the compound. Thisreaction can be carried out by, for example, a method described inComprehensive Organic Transformations (Second Edition, 1999, John Wiley& Sons, Inc., pp. 1978-1982).

(Step A-3)

Step A-3 is the step of reacting the compound (4) obtained in the stepA-2 with compound (5) in the presence of a base to produce compound (I).The compound (5) is known in the art or is easily obtained from acompound known in the art. The compound (I) of interest of this step canalso be converted, if necessary, to another compound (I) of interestthrough deprotection reaction. The reaction for converting the obtainedcompound (I) of interest to another compound (I) of interest by theremoval of the protective group is not particularly limited as long asthe reaction does not influence the other parts of the compound. Thisreaction can be carried out according to a routine method, for example,a method described in T. W. Greene, P. G. M. Wuts, Protective Groups inOrganic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.

Hereinafter, this step is referred to as step A-3-1 when L¹ is a nitrogroup, as step A-3-2 when L¹ is an amino group, and as step A-3-3 whenL¹ is a halogeno group.

(Step A-3-1)

When L¹ is a nitro group, step A-3-1 comprises:

(step A-3-1a): the step of selectively reducing the nitro group of thecompound obtained in the step A-2 into an amino group; and

(step A-3-1b): the step of reacting the compound obtained in the stepA-3-1a with compound (5) in the presence of a base to produce compound(I).

(Step A-3-1a)

The method for selectively reducing the nitro group is not particularlylimited as long as the method does not influence the other parts of thecompound. This method can be generally carried out by a method wellknown in the techniques of organic synthetic chemistry, for example, amethod described in Comprehensive Organic Transformations (SecondEdition, 1999, John Wiley & Sons, Inc., pp. 821-828). The method ispreferably a catalytic reduction method or a method using a combinationof a reducing agent and an additive.

Examples of the metal catalyst for use in the catalytic reduction methodcan include: palladium catalysts such as palladium on carbon, palladiumblack, palladium hydroxide on carbon, and palladium on barium sulfate;platinum catalysts such as platinum oxide and platinum black, platiniumon carbon; rhodium catalysts such as rhodium on aluminum oxide andchlorotris(triphenylphosphine)rhodium (I); and nickel catalysts such asRaney nickel. The metal catalyst is preferably a palladium catalyst,more preferably 10% palladium on carbon.

The hydrogen pressure in the catalytic reduction method is preferably 1to 10 atm, more preferably 1 atm.

The solvent for use in the catalytic reduction method is notparticularly limited as long as the solvent is inert to this reaction.Examples thereof can include aliphatic hydrocarbons, aromatichydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters,nitriles, ketones, amides, and mixtures thereof. The solvent ispreferably an alcohol, an ether, an amide, or a mixture thereof, morepreferably methanol or a mixture of tetrahydrofuran and ethanol.

The reaction temperature in the catalytic reduction method is preferablyroom temperature to 60° C.

The reaction time in the catalytic reduction method is preferably 1 hourto 24 hours.

The combination of the reagents for use in the reaction using thecombination of the reducing agent and the additive is preferably acombination of sodium borohydride and nickel(II) chloride hexahydrate, acombination of zinc powder and acetic acid, a combination of iron powderand acetic acid, or a combination of tin(II) chloride and hydrochloricacid, more preferably a combination of sodium borohydride and nickel(II)chloride hexahydrate.

The solvent for use in the reaction using the combination of thereducing agent and the additive is preferably a mixture of an alcoholand an ether, more preferably a mixture of tetrahydrofuran and methanol.

The reaction temperature in the reaction using the combination of thereducing agent and the additive is preferably 0° C. to room temperature.

The reaction time in the reaction using the combination of the reducingagent and the additive is preferably 5 minutes to 2 hours.

(Step A-3-1b)

Examples of the base used can include alkali metal carbonates, alkalimetal bicarbonates, alkali metal hydrides, alkali metal hydroxides,alkali metal alkoxides, lithium amides, alkali metal silylamides, andorganic amines. The base is preferably an organic amine, more preferablypyridine.

Examples of the solvent used can include aliphatic hydrocarbons,aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters,nitriles, ketones, and amides. Alternatively, the solvent may not beused. Preferably, the solvent is not used.

The reaction temperature is preferably 0° C. to 100° C., more preferablyroom temperature to 80° C.

The reaction time is preferably 15 minutes to 24 hours, more preferably30 minutes to 3 hours.

The reaction for converting the obtained compound (I) of interestobtained in this step to another compound (I) of interest by the removalof the protective group is not particularly limited as long as thereaction does not influence the other parts of the compound. Thisreaction can be carried out according to a routine method, for example,a method described in T. W. Greene, P. G. M. Wuts, Protective Groups inOrganic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.

(Step A-3-2)

When L¹ is an amino group, the compound (I) can be produced according tothe step A-3-1b.

(Step A-3-3)

When L¹ is a halogeno group, step A-3-3 comprises:

(step A-3-3a): the step of converting the bromo group of the compoundproduced in the step A-2 to a N-Boc amide group using a metal catalystin the presence of a base;

(step A-3-3b): the step of deprotecting the N-Boc group of the compoundobtained in the step A-3-3a to form an amino group; and

(step A-3-3c): the step of reacting the compound obtained in the stepA-3-3b with compound (5) in the presence of a base to produce compound(I).

(Step A-3-3a)

The method for converting the bromo group on the aromatic ring to aN-Boc amide group is not particularly limited as long as the method doesnot influence the other parts of the compound. This method can becarried out according to a method well known in the techniques oforganic synthetic chemistry, for example, a method described in A. P.Dishington, P. D. Johnson, J. G. Kettle, Tetrahedron Letters, 45, 3733(2004) or S. Bhagwanth, A. G. Waterson, G. M. Adjabeng, K. R.Hornberger, Journal of Organic Chemistry, 74, 4634 (2009).

The metal catalyst used is preferably a combination oftris(dibenzylideneacetone)dipalladium(0) chloroform complex and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos™) or acombination of tris(dibenzylideneacetone)dipalladium(0) chloroformcomplex and di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine(tBuXPhos™).

The base used is preferably an alkali metal carbonate, an alkali metalphosphate, or an alkali metal alkoxide, more preferably potassiumcarbonate, cesium carbonate, potassium phosphate, or sodiumtert-butoxide.

Examples of the solvent used can include aliphatic hydrocarbons,aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,esters, nitriles, ketones, amides, and mixtures thereof. The solvent ispreferably an aromatic hydrocarbon, an ether, a nitrile, or an amide,more preferably toluene, 1,4-dioxane, acetonitrile, orN,N-dimethylformamide.

The reaction temperature is preferably room temperature to 100° C.

The reaction time is preferably 1 hour to 48 hours.

(Step A-3-3b)

The method for deprotecting the N-Boc group is not particularly limitedas long as the method does not influence the other parts of thecompound. This method can be carried out according to a routine method,for example, a method described in T. W. Greene, P. G. M. Wuts,Protective Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley& Sons, Inc., pp. 725-735.

(Step A-3-3c)

The compound (I) can be produced according to the step A-3-1b.

When L¹ is a bromo group, the compound (I) can also be produced throughthe reaction of the compound (4) with the following compound (6):

using a metal catalyst in the presence of a base.

The method for converting the bromo group on the aromatic ring to abenzenesulfonamide group is not particularly limited as long as themethod does not influence the other parts of the compound. This methodcan be carried out according to a method well known in the techniques oforganic synthetic chemistry, for example, a method described in X. Wang,A. Guram, M. Ronk, J. E. Milne, J. S. Tedrow, M. M. Faul, TetrahedronLetters, 53, 7 (2012), W. Deng, L. Liu, C. Zhang, M. Liu, Q.-X. Guo,Tetrahedron Letters, 46, 7295 (2005), or D. K. Luci, J. B. Jameson, A.Yasgar, G. Diaz, N. Joshi, A. Kantz, K. Markham, S. Perry, N. Kuhn, J.Yeung, E. H. Kerns, L. Schultz, M. Holinstat, J. Nadler, D. A.Taylor-Fishwick, A. Jadhav, A. Simeonov, T. R. Holman, D. J. Maloney,Journal of Medicinal Chemistry, 57, 495 (2014).

The metal catalyst used is preferably a combination of copper(I) iodideand N-methyl-2-(methylamino)ethylamine.

The base used is preferably an alkali metal carbonate, an alkali metalphosphate, or an alkali metal alkoxide, more preferably potassiumcarbonate or cesium carbonate.

Examples of the solvent used can include aliphatic hydrocarbons,aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,esters, nitriles, ketones, amides, and mixtures thereof. The solvent ispreferably an aromatic hydrocarbon, an ether, a nitrile, or an amide,more preferably xylene, 1,4-dioxane, acetonitrile, orN,N-dimethylformamide.

The reaction temperature is preferably room temperature to 100° C.

The reaction time is preferably 1 hour to 48 hours.

When the compound represented by the general formula (I) of the presentinvention or the pharmacologically acceptable salt thereof is used as apharmaceutical, the compound or the salt can be administered alone(i.e., as a bulk) or can be administered orally as an appropriatepharmaceutically acceptable preparation such as a tablet, a capsule,granules, a powder, or a syrup or parenterally as an appropriatepharmaceutically acceptable preparation such as an injection, asuppository, or a patch (preferably orally).

These preparations are produced by well-known methods using additivessuch as excipients, binders, disintegrants, lubricants, emulsifiers,stabilizers, corrigents, diluents, solvents for injections, oleaginousbases, and water-soluble bases.

Examples of the excipients can include organic excipients and inorganicexcipients. Examples of the organic excipients can include: sugarderivatives such as lactose, saccharose, glucose, mannitol, andsorbitol; starch derivatives such as corn starch, potato starch,α-starch, dextrin, and carboxymethyl starch; cellulose derivatives suchas crystalline cellulose, low-substituted hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose,carboxymethylcellulose calcium, and internally cross-linkedcarboxymethylcellulose sodium; gum arabic; dextran; and pullulan.Examples of the inorganic excipients can include: light anhydroussilicic acid and silicate derivatives such as synthetic aluminumsilicate and calcium silicate; phosphates such as calcium phosphate; andsulfates such as calcium sulfates.

Examples of the binders can include: the excipients listed above;gelatin; polyvinylpyrrolidone; and polyethylene glycol.

Examples of the disintegrants can include: the excipients listed above;chemically modified starch or cellulose derivatives such ascroscarmellose sodium and carboxymethyl starch sodium; and cross-linkedpolyvinylpyrrolidone.

Examples of the lubricants can include: talc; stearic acid; stearic acidmetal salts such as calcium stearate and magnesium stearate; colloidalsilica; waxes such as bees wax and spermaceti; boric acid; glycol;D,L-leucine; carboxylic acids such as fumaric acid and adipic acid;carboxylic acid sodium salts such as sodium benzoate; sulfates such assodium sulfate; lauryl sulfates such as sodium lauryl sulfate andmagnesium lauryl sulfate; silicic acids such as silicic anhydride andsilicic acid hydrate; and the starch derivatives listed as theexcipients.

Examples of the emulsifiers can include: colloidal clay such asbentonite and veegum; anionic surfactants such as sodium lauryl sulfateand calcium stearate; cationic surfactants such as benzalkoniumchloride; and nonionic surfactants such as polyoxyethylene alkyl ether,polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester.

Examples of the stabilizers can include: p-hydroxybenzoic acid esterssuch as methylparaben and propylparaben; alcohols such as chlorobutanol,benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenolssuch as phenol and cresol; thimerosal; dehydroacetic acid; and sorbicacid.

Examples of the corrigents can include sweeteners, acidulants, andflavors usually used.

Examples of the diluents can include water, ethanol, propylene glycol,ethoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acidesters.

Examples of the solvents for injections can include water, ethanol, andglycerin.

Examples of the oleaginous bases can include cacao butter, laurinbutter, coconut oil, palm kernel oil, camellia oil, liquid paraffin,white petrolatum, purified lanoline, glycerin monostearate,polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester,sucrose fatty acid ester, stearyl alcohol, and cetanol.

Examples of the water-soluble bases can include glycerin, polyethyleneglycol, ethanol, and purified water.

The dose of the compound represented by the general formula (I) of thepresent invention or the pharmacologically acceptable salt thereofserving as an active ingredient differs depending on the symptoms andage of a patient, etc. The single dose thereof is 0.001 mg/kg(preferably 0.01 mg/kg) as the lower limit and 10 mg/kg (preferably 1mg/kg) as the upper limit for oral administration and 0.001 mg/kg(preferably 0.01 mg/kg) as the lower limit and 10 mg/kg (preferably 1mg/kg) as the upper limit for parenteral administration and can beadministered once to six times a day according to the symptoms.

The compound of the present invention can be used in combination withany of various therapeutic or prophylactic agents for the aforementioneddisease for which the compound of the present invention is probablyeffective. In this combined use, the compound of the present inventionand the agent may be administered simultaneously, separately butcontinuously, or at the desired time interval. The preparations to beadministered simultaneously may be formulated as a combination drug orformulated as separate preparations.

The pyridine compound or the pharmacologically acceptable salt thereof,which is the compound of the present invention, has an excellent TNAPinhibitory effect and is useful as a therapeutic or prophylactic agentfor pseudoxanthoma elasticum (PXE), generalized arterial calcificationof infancy (GACI), craniometaphyseal dysplasia (CMD), ossification ofthe yellow ligament (OYL), arterial calcification due to deficiency ofCD73 (ACDC), arthrosis deformans, osteoarthritis, ankylosis of thejoint, idiopathic infantile arterial calcification (IIAC), ankylosingspondylitis (AS), tumoral calcinosis (TC), progressive osseousheteroplasia (POH), Keutel syndrome, vascular calcification associatedwith chronic renal failure (including glomerulonephritis, IgAnephropathy, hypertensive nephropathy, and diabetic nephropathy) andsecondary parathyroid hyperplasia, metastatic calcification,calciphylaxis, calcific tendinitis of the longus colli muscle,fibrodysplasia ossificans progressiva (FOP), calcific aortic stenosis,pericarditis calculosa, atherosclerotic vascular calcification, calcificuremic arteriopathy (CUA), Kawasaki disease, calcification due toobesity and aging, tibial arterial calcification, bone metastasis,prosthetic calcification, Paget's disease, or peritoneal calcification.Moreover, the compound of the present invention has low toxicity andexcellent safety and as such, is very useful as a pharmaceutical.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Hereinafter, the present invention will be described in more detail withreference to Examples, etc. However, the scope of the present inventionis not intended to be limited by them.

The chemical structural formulas described in Examples represent thechemical structures of corresponding compounds in a free form.

Elution in column chromatography in Examples was carried out underobservation by thin layer chromatography (TLC). In the TLC observation,silica gel 60F₂₅₄ manufactured by Merck KGaA was used as a TLC plate; asolvent used as an eluting solvent in column chromatography was used asa developing solvent; and a UV detector or a chromogenic method using acoloring agent (e.g., a ninhydrin coloring solution, an anisaldehydecoloring solution, an ammonium phosphomolybdate coloring solution, acerium ammonium nitrate (CAM) coloring solution, or an alkalinepermanganate coloring solution) was used as a detection method. Silicagel SK-85 (230-400 mesh) also manufactured by Merck KGaA, silica gel 60N (40-50 μm) manufactured by Kanto Chemical Co., Inc., or Chromatorex NH(200-350 mesh) manufactured by Fuji Silysia Chemical Ltd. was used assilica gel for columns. In addition to general column chromatography, anautomatic chromatography apparatus (Purif-α2 or Purif-espoir2)manufactured by Shoko Scientific Co., Ltd., an automatic chromatographyapparatus (W-Prep 2XY) manufactured by Yamazen Corp., an automaticchromatography apparatus (Isolera One) manufactured by Biotage JapanLtd., or an automatic chromatography apparatus (CombiFlash Rf)manufactured by Teledyne Isco, Inc. was appropriately used. The elutingsolvent was determined on the basis of the TLC observation.

In Examples, nuclear magnetic resonance (¹H NMR) spectra were indicatedby chemical shift δ values (ppm) determined with tetramethylsilane as astandard. Splitting patterns were indicated by s for singlet, d fordoublet, t for triplet, q for quartet, m for multiplet, and br forbroad. Mass spectrometry (hereinafter, referred to as MS) was conductedby the electron ionization (EI), electron spray ionization (ESI),atmospheric pressure chemical ionization (APCI), electron sprayatmospheric pressure chemical ionization (ES/APCI), or fast atombombardment (FAB) method.

In each step of Examples, the adjustment of a reaction solution andreaction were carried out at room temperature unless the temperature isotherwise specified.

EXAMPLES (Example 1)5-Chloro-2-methoxy-N-(4-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

(1a) 2-Chloro-N-(2-hydroxyethyl)-N-methyl-5-nitropyridine-3-carboxamide

To a suspension of 2-chloro-5-nitropyridine-3-carboxylic acid (500 mg,2.47 mmol) in methylene chloride (10 mL), oxalyl chloride (0.28 mL, 3.3mmol) and N,N-dimethylformamide (0.05 mL, 0.64 mmol) were added at roomtemperature, and the mixture was stirred at the same temperature asabove for 2 hours. The reaction mixture was concentrated under reducedpressure to prepare a crude product of2-chloro-5-nitropyridine-3-carboxylic acid chloride. To a solution of2-(methylamino)ethanol (0.197 mL, 2.47 mmol) andN,N-diisopropylethylamine (0.84 mL, 4.9 mmol) in tetrahydrofuran (5 mL),a solution of the crude product of 2-chloro-5-nitropyridine-3-carboxylicacid chloride in tetrahydrofuran (5 mL) was added over 10 minutes underice cooling, and the mixture was stirred at room temperature for 1 hour.The reaction mixture was diluted with ethyl acetate, washed with asaturated aqueous solution of sodium chloride, and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (n-hexane/ethyl acetate=100/0-0/100) to obtainthe title compound (494.3 mg, yield: 77%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.30-9.22 (1H, m), 8.58-8.46 (1H,m), 4.00-3.68 (4H, m), 3.24-2.99 (3H, m).

(1b) 4-Methyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

To a suspension of2-chloro-N-(2-hydroxyethyl)-N-methyl-5-nitropyridine-3-carboxamide(259.2 mg, 1.00 mmol) obtained in Example (1a) in tetrahydrofuran (50mL), sodium hydride (63% content, 68.8 mg, 1.81 mmol) was added underice cooling, and the mixture was stirred at room temperature for 22hours. The reaction mixture was cooled in an ice water bath. A 1 Naqueous sodium hydroxide solution (10 mL) was added thereto, and themixture was stirred at room temperature for 20 minutes. The reactionmixture was diluted by addition of ethyl acetate, and the organic layerwas separated and dried over anhydrous sodium sulfate. After filtration,the solvent was distilled off under reduced pressure to obtain the titlecompound (173.3 mg, yield: 78%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.35 (1H, d, J=3.0 Hz), 9.23 (1H, d,J=3.0 Hz), 4.76-4.70 (2H, m), 3.83-3.73 (2H, m), 3.27 (3H, s).

(1c) 7-Amino-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

To a mixture of4-methyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (173.3mg, 0.78 mmol) obtained in Example (1b) in tetrahydrofuran (5 L) andmethanol (5 mL), nickel(II) chloride hexahydrate (386 mg, 1.62 mmol) wasadded. Subsequently, the mixture was cooled in an ice water bath. Sodiumborohydride (122 mg, 3.22 mmol) was added thereto over 10 minutes, andthen, the mixture was stirred at room temperature for 30 minutes. Thereaction mixture was diluted by addition of acetone and a saturatedaqueous solution of sodium bicarbonate, further Celite 545(R)(approximately 0.6 g) was added thereto, and the mixture was stirred atroom temperature for 30 minutes. The reaction mixture was filtered, andthe filtrate was concentrated under reduced pressure. The residue waspurified by reverse-phase silica gel column chromatography (ChromatorexODS 100-200 mesh 50 mL, water/methanol=100/0-70/30) to obtain the titlecompound (96.4 mg, yield: 64%).

¹H NMR spectrum (CD₃OD, 400 MHz) δ: 7.77 (1H, d, J=3.0 Hz), 7.47 (1H, d,J=3.0 Hz), 4.44 (2H, t, J=5.2 Hz), 3.61 (2H, t, J=5.2 Hz), 3.19 (3H, s).

(1d)5-Chloro-2-methoxy-N-(4-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

To a mixture of7-amino-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (40.0mg, 0.21 mmol) obtained in Example (1c) and pyridine (1.0 mL, 12.4mmol), 5-chloro-2-methoxybenzenesulfonyl chloride (56.5 mg, 0.23 mmol)was added, and the mixture was stirred at 80° C. for 2 hours in an oilbath. The reaction mixture was cooled and then concentrated underreduced pressure, and the residue was purified in an automaticchromatography apparatus (ethyl acetate/methanol=100/0-80/20). Theobtained solid was suspended by the addition of diisopropyl ether (1mL), and then, the solid was collected by filtration and dried to obtainthe title compound (31.9 mg, yield: 39%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.28 (1H, d, J=2.4 Hz), 8.08 (1H, d,J=3.0 Hz), 7.74 (1H, d, J=2.4 Hz), 7.47 (1H, dd, J=8.8, 2.7 Hz),7.02-6.98 (2H, m), 4.53 (2H, t, J=4.6 Hz), 4.08 (3H, s), 3.64 (2H, t,J=4.3 Hz), 3.19 (3H, s).

MS spectrum (ES/APCI⁺): 398 (M+H), 400 (M+2+H).

(Example 2)5-Fluoro-2-methoxy-N-(4-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

To a mixture of7-amino-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (96.4mg, 0.50 mmol) obtained in Example (1c) and pyridine (2.0 mL, 24.9mmol), 5-fluoro-2-methoxybenzenesulfonyl chloride (124.4 mg, 0.56 mmol)was added, and the mixture was stirred at 80° C. for 70 minutes in anoil bath. The reaction mixture was cooled and then concentrated underreduced pressure, and the residue was purified in an automaticchromatography apparatus (ethyl acetate/methanol=100/0-85/15). Theobtained solid was suspended by the addition of diisopropyl ether (1mL), and then, the solid was collected by filtration and dried to obtainthe title compound (145.4 mg, yield: 76%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.27 (1H, d, J=2.4 Hz), 8.08 (1H, d,J=3.0 Hz), 7.50 (1H, dd, J=7.3, 3.0 Hz), 7.25-7.20 (1H, m), 7.07 (1H,s), 7.02 (1H, dd, J=9.1, 4.3 Hz), 4.52 (2H, t, J=4.6 Hz), 4.06 (3H, s),3.63 (2H, t, J=4.6 Hz), 3.19 (3H, s).

MS spectrum (ES/APCI⁺): 382 (M+H).

(Example 3)5-Chloro-N-(4-ethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-methoxybenzenesulfonamide

(3a) 4-Ethyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (288 mg, yield for 2 steps: 49%) was obtained byproduction according to Examples (1a) and (1b) using2-chloro-5-nitropyridine-3-carboxylic acid (502 mg, 2.47 mmol) and2-(ethylamino)ethanol (223 mg, 2.50 mmol) as starting materials.

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.34 (1H, d, J=3.0 Hz), 9.22 (1H, d,J=3.0 Hz), 4.71-4.69 (2H, m), 3.76-3.74 (2H, m), 3.69 (2H, q, J=7.3 Hz),1.26 (3H, t, J=7.3 Hz).

(3b) 7-Amino-4-ethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

A mixture of4-ethyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (288 mg,1.22 mmol) obtained in Example (3a) and 10% palladium carbon (watercontent: 54.6%, 31 mg) in methanol (15 mL) was stirred at roomtemperature for 5 hours at normal pressure under the hydrogenatmosphere. Hydrogen in the reaction container was replaced withnitrogen, and then, the reaction mixture was filtered through pad ofCelite 545(R). The solvent in the filtrate was distilled off underreduced pressure to obtain the title compound (247 mg, yield: 98%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.88 (1H, d, J=3.0 Hz), 7.60 (1H, d,J=3.0 Hz), 4.47 (2H, t, J=4.9 Hz), 3.68-3.63 (4H, m), 3.55 (2H, t, J=4.9Hz), 1.25 (3H, t, J=7.3 Hz).

(3c)5-Chloro-N-(4-ethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-methoxybenzenesulfonamide

The title compound (222 mg, yield: 90%) was obtained by productionaccording to Example (1d) using7-amino-4-ethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (124 mg,0.60 mmol) obtained in Example (3b) and5-chloro-2-methoxybenzenesulfonyl chloride (159 mg, 0.66 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.26 (1H, d, J=2.4 Hz), 8.07 (1H, d,J=3.0 Hz), 7.74 (1H, d, J=2.4 Hz), 7.47 (1H, dd, J=8.8, 2.7 Hz),7.05-6.98 (2H, m), 4.52 (2H, t, J=4.3 Hz), 4.08 (3H, s), 3.65-3.59 (4H,m), 1.22 (3H, t, J=7.0 Hz).

MS spectrum (ES/APCI⁺): 412 (M+H), 414 (M+2+H).

(Example 4)N-(4-Ethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-5-fluoro-2-methoxybenzenesulfonamide

The title compound (206 mg, yield: 88%) was obtained by productionaccording to the method described in Example (1d) using7-amino-4-ethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (123 mg,0.59 mmol) obtained in Example (3b) and5-fluoro-2-methoxybenzenesulfonyl chloride (150 mg, 0.67 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.26 (1H, d, J=3.0 Hz), 8.08 (1H, d,J=2.4 Hz), 7.50 (1H, dd, J=7.6, 3.3 Hz), 7.25-7.21 (1H, m), 7.10-7.07(1H, m), 7.02 (1H, dd, J=9.1, 3.6 Hz), 4.51 (2H, t, J=4.6 Hz), 4.06 (3H,s), 3.65-3.58 (4H, m), 1.22 (3H, t, J=7.3 Hz).

MS spectrum (ES/APCI⁺): 396 (M+H).

(Example 5)5-Chloro-2-methoxy-N-[5-oxo-4-(propan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

(5a) 5-Chloro-2-methoxybenzenesulfonamide

To a solution of 5-chloro-2-methoxybenzenesulfonyl chloride (3 g, 12.4mmol) in tetrahydrofuran (20 mL), a 28% aqueous ammonia solution (20 mL,295 mmol) was added, and the mixture was stirred at room temperature for19 hours. The reaction mixture was diluted by addition of 1 Nhydrochloric acid, followed by extraction with ethyl acetate. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride and dried over anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure toobtain the title compound (2.74 g, yield: quantitative).

¹H NMR spectrum (CDCl3, 400 MHz) δ: 7.91 (1H, d, J=3.0 Hz), 7.56-7.46(1H, m), 7.00 (1H, d, J=8.5 Hz), 5.06 (2H, br s), 4.02 (3H, s).

(5b)5-Bromo-2-chloro-N-(2-hydroxyethyl)-N-(propan-2-yl)pyridine-3-carboxamide

The title compound (1.20 g, yield: 88%) was obtained by productionaccording to the method described in Example (1a) using5-bromo-2-chloropyridine-3-carboxylic acid (1.00 g, 4.22 mmol) and2-(propan-2-ylamino)ethanol (481 mg, 4.66 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.51-8.46 (1H, m), 7.82-7.73 (1H,m), 3.96-3.85 (2H, m), 3.72-3.54 (3H, m), 3.31-3.25 (1H, m), 1.38-1.09(6H, m).

(5c)7-Bromo-4-(propan-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

To a solution of5-bromo-2-chloro-N-(2-hydroxyethyl)-N-(propan-2-yl)pyridine-3-carboxamide(600 mg, 1.87 mmol) obtained in Example (5b) in N,N-dimethylformamide(20 mL), sodium hydride (63% content, 141 mg, 3.70 mmol) was added underice cooling, and the mixture was stirred at 80° C. for 3 hours and 20minutes in an oil bath. The reaction mixture was cooled and diluted byaddition of a saturated aqueous solution of sodium chloride, followed byextraction with ethyl acetate. The organic layer was washed with a 5%aqueous sodium chloride solution three times and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (hexane/ethyl acetate=100/0-0/100) to obtainthe title compound (142 mg, yield: 27%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.48-8.47 (1H, m), 8.43-8.42 (1H,m), 5.06-4.99 (1H, m), 4.52 (2H, t, J=4.6 Hz), 3.52 (2H, t, J=4.6 Hz),1.21 (6H, d, J=6.7 Hz).

(5d)5-Chloro-2-methoxy-N-[5-oxo-4-(propan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

A mixture of7-bromo-4-(propan-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(142 mg, 0.50 mmol) obtained in Example (5c),5-chloro-2-methoxybenzenesulfonamide (114 mg, 0.51 mmol) obtained inExample (5a), potassium carbonate (145 mg, 1.05 mmol),N,N′-dimethylethylene-1,2-diamine (0.27 mL, 2.5 mmol), and copper(I)iodide (48.8 mg, 0.26 mmol) in acetonitrile (5 mL) was heated to refluxfor 6 hours and 30 minutes in an oil bath. The reaction mixture wascooled, diluted by addition of 1 N hydrochloric acid, and then stirredat room temperature for 30 minutes. The reaction mixture was filteredthrough pad of Celite 545(R), and the filtrate was subjected toextraction with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (ethyl acetate/methanol=100/0-85/15). Theobtained solid was suspended by the addition of diisopropyl ether, andthen, the solid was collected by filtration and dried to obtain thetitle compound (44.4 mg, yield: 21%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.25 (1H, d, J=2.4 Hz), 8.03 (1H, d,J=2.4 Hz), 7.75 (1H, d, J=3.0 Hz), 7.48 (1H, dd, J=8.8, 2.7 Hz),7.02-6.98 (2H, m), 5.02-4.95 (1H, m), 4.47 (2H, t, J=4.6 Hz), 4.08 (3H,s), 3.48 (2H, t, J=4.6 Hz), 1.19 (6H, d, J=6.7 Hz).

MS spectrum (ES/APCI⁺): 426 (M+H), 428 (M+2+H).

(Example 6)5-Chloro-N-[4-(2-hydroxyethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

(6a)4-(2-Hydroxyethyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (318 mg, yield for 2 steps: 51%) was obtained byproduction according to the method described in Examples (1a) and (1b)using 2-chloro-5-nitropyridine-3-carboxylic acid (501 mg, 2.47 mmol) and2,2-iminodiethanol (257 mg, 2.44 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.24 (1H, d, J=2.4 Hz), 8.56 (1H, d,J=2.4 Hz), 4.23-4.14 (1H, m), 4.06-3.96 (1H, m), 3.90-3.82 (2H, m),3.73-3.59 (2H, m), 3.44-3.32 (1H, m), 3.06-3.00 (1H, m), 2.53-2.47 (1H,m).

(6b)7-Amino-4-(2-hydroxyethyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (125 mg, yield: 90%) was obtained by productionaccording to the method described in Example (3c) using4-(2-hydroxyethyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(158 mg, 0.62 mmol) obtained in Example (6a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.90 (1H, d, J=3.0 Hz), 7.58 (1H, d,J=3.0 Hz), 4.52 (2H, t, J=4.9 Hz), 3.92-3.88 (2H, m), 3.81-3.78 (2H, m),3.68-3.65 (3H, m).

(6c)5-Chloro-N-[4-(2-hydroxyethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

The title compound (199 mg, yield: 83%) was obtained by productionaccording to Example (1d) using7-amino-4-(2-hydroxyethyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(125 mg, 0.56 mmol) obtained in Example (6b) and5-chloro-2-methoxybenzenesulfonyl chloride (150 mg, 0.62 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.34 (1H, s), 8.08 (1H, d, J=3.0Hz), 7.94 (1H, d, J=3.0 Hz), 7.70-7.62 (2H, m), 7.26 (1H, dd, J=10.9,2.4 Hz), 4.82-4.79 (1H, m), 4.44 (2H, t, J=4.6 Hz), 3.87 (3H, s), 3.63(2H, t, J=4.6 Hz), 3.59-3.51 (4H, m).

MS spectrum (ES/APCI⁺): 428 (M+H), 430 (M+2+H).

(Example 7)5-Chloro-2-methoxy-N-[4-(2-methoxyethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

(7a)4-(2-Methoxyethyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

To a solution of4-(2-hydroxyethyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(158 mg, 0.62 mmol) obtained in Example (6a) in tetrahydrofuran (4 mL),methyl iodide (0.062 mL, 1.0 mmol) and sodium hydride (63%, 32 mg, 0.84mmol) were added under ice cooling, and the mixture was stirred at roomtemperature for 4 hours. To the mixture, methyl iodide (0.1 mL, 1.6mmol) and sodium hydride (63%, 80 mg, 2.1 mmol) were further added, andthe mixture was stirred at room temperature for 20 hours. Methyl iodide(0.1 mL, 1.6 mmol) and sodium hydride (63%, 60 mg, 1.6 mmol) werefurther added thereto, and the mixture was stirred at room temperaturefor 7 hours and 30 minutes. The reaction mixture was diluted by additionof a saturated aqueous solution of sodium chloride, followed byextraction with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (ethyl acetate/methanol=100/0-85/15) to obtainthe title compound (76.7 mg, yield: 46%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.30 (1H, d, J=3.0 Hz), 9.23 (1H, d,J=3.0 Hz), 4.72 (2H, t, J=3.9 Hz), 3.87-3.84 (2H, m), 3.81 (2H, t, J=4.9Hz), 3.65 (2H, t, J=4.9 Hz), 3.37 (3H, s).

(7b)7-Amino-4-(2-methoxyethyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (65.3 mg, yield: 96%) was obtained by productionaccording to the method described in Example (3c) using4-(2-methoxyethyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(76.7 mg, 0.29 mmol) obtained in Example (7a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.88 (1H, d, J=3.0 Hz), 7.58 (1H, d,J=3.0 Hz), 4.49 (2H, t, J=5.2 Hz), 3.78 (2H, t, J=4.9 Hz), 3.67-3.61(6H, m), 3.37 (3H, s).

(7c)5-Chloro-2-methoxy-N-[4-(2-methoxyethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

The title compound (86.9 mg, yield: 72%) was obtained by productionaccording to Example (1d) using7-amino-4-(2-methoxyethyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(65.3 mg, 0.28 mmol) obtained in Example (7b) and5-chloro-2-methoxybenzenesulfonyl chloride (81.5 mg, 0.34 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.25 (1H, d, J=2.4 Hz), 8.07 (1H, d,J=2.4 Hz), 7.75 (1H, d, J=2.4 Hz), 7.47 (1H, dd, J=8.8, 2.7 Hz),7.15-7.11 (1H, m), 7.00 (1H, d, J=8.5 Hz), 4.56-4.52 (2H, m), 4.06 (3H,s), 3.76-3.70 (4H, m), 3.61 (2H, t, J=4.9 Hz), 3.35 (3H, s).

MS spectrum (ES/APCI⁺): 442 (M+H), 444 (M+2+H).

(Example 8)5-Chloro-N-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

(8a) 2-[(2,4-Dimethoxybenzyl)amino]ethanol

To a mixture of 2,4-dimethoxybenzaldehyde (16.20 g, 97.5 mmol) and2-aminoethanol (5.98 g, 97.9 mmol) in methanol (120 mL), anhydroussodium sulfate (6.23 g, 43.9 mmol) was added, and the mixture wasstirred at room temperature for 20 hours. Subsequently, to the mixture,sodium borohydride (1.84 g, 48.6 mmol) was added over 15 minutes, andthe mixture was stirred at 22° C. for 30 minutes. To the reactionmixture, acetic acid (2.8 mL, 49 mmol) was added, and the mixture wasstirred for 10 minutes and concentrated into approximately ½ of theamount under reduced pressure. The concentrated mixture was diluted byaddition of water and a saturated aqueous solution of sodiumbicarbonate, followed by extraction with methylene chloride. The organiclayer was washed with a saturated aqueous solution of sodium chlorideand dried over anhydrous sodium sulfate. After filtration, the solventwas distilled off under reduced pressure. To the residue, n-hexane (100mL) and ethyl acetate (4 mL) were added, and the precipitated solid wascollected by filtration, washed with n-hexane, and then dried to obtainthe title compound (18.44 g, yield: 90%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.12 (1H, d, J=8.2 Hz), 6.47-6.42(2H, m), 3.82 (3H, s), 3.80 (3H, s), 3.74 (2H, S), 3.65-3.63 (2H, m),2.76-2.74 (2H, m).

(8b)2-Chloro-N-(2,4-dimethoxybenzyl)-N-(2-hydroxyethyl)-5-nitropyridine-3-carboxamide

To a suspension of 2-chloro-5-nitropyridine-3-carboxylic acid (4.91 g,24.2 mmol) and oxalyl chloride (2.6 mL, 30 mmol) in methylene chloride(120 mL), N,N-dimethylformamide (0.10 mL, 1.3 mmol) was added at roomtemperature, and the mixture was stirred at the same temperature asabove for 30 minutes. The reaction mixture was concentrated underreduced pressure to prepare a crude product of2-chloro-5-nitropyridine-3-carboxylic acid chloride. To a solution of2-[(2,4-dimethoxybenzyl)amino]ethanol (5.11 g, 24.2 mmol) obtained inExample (8a) and N,N-diisopropylethylamine (8.25 mL, 48.5 mmol) intetrahydrofuran (50 mL), a solution of the crude product of2-chloro-5-nitropyridine-3-carboxylic acid chloride in tetrahydrofuran(70 mL) was added over 20 minutes under ice cooling, and the reactionmixture was stirred at the same temperature as above for 90 minutes. Tothe reaction mixture, water (0.05 mL) was added, and then, the mixturewas concentrated under reduced pressure. The concentrated mixture wasdiluted by addition of water, followed by extraction with ethyl acetate.The organic layer was washed with water and a saturated aqueous solutionof sodium chloride, and anhydrous magnesium sulfate and charcoal wereadded thereto. After filtration through pad of Celite 545 (R), thesolvent was distilled off under reduced pressure. To the residue,diisopropyl ether (50 mL) and ethyl acetate (10 mL) were added toprecipitate a solid. The suspension was stirred at room temperature for30 minutes. The precipitated solid was collected by filtration, washedwith a mixed solvent of diisopropyl ether/ethyl acetate=5/1, and thendried to obtain the title compound (8.30 g, yield: 87%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.24 (0.8H, d, J=2.7 Hz), 9.21(0.2H, d, J=2.7 Hz), 8.57 (0.2H, d, J=2.7 Hz), 8.44 (0.8H, d, J=2.7 Hz),7.38 (0.2H, d, J=8.2 Hz), 6.99 (0.8H, d, J=8.2 Hz), 6.54-6.48 (0.4H, m),6.45-6.40 (1.6H, m), 5.13 (0.2H, d, J=14.9 Hz), 4.53 (0.2H, d, J=14.9Hz), 4.38-3.54 (10.8H, m), 3.24-3.19 (0.4H, t, J=5.1 Hz), 2.42 (0.4H, t,J=5.1 Hz).

(8c)4-(2,4-Dimethoxybenzyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (ca.1.9 mol/L, 14.4 mL, 27.4 mmol) was diluted with tetrahydrofuran (450mL). A solution of2-chloro-N-(2,4-dimethoxybenzyl)-N-(2-hydroxyethyl)-5-nitropyridine-3-carboxamide(7.22 g, 18.2 mmol) obtained in Example (8b) in tetrahydrofuran (450 mL)was added thereto over 70 minutes under ice cooling, and the mixture wasstirred at the same temperature as above for 10 minutes and furtherstirred at room temperature for 30 minutes. To the reaction mixture, asaturated aqueous solution of ammonium chloride (100 mL) was added, andthen, the reaction mixture was concentrated into approximately ⅕ of theamount under reduced pressure. The concentrated mixture was diluted byaddition of water, followed by extraction with ethyl acetate twice. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride and dried over anhydrous magnesium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure, andthe residue was purified by silica gel column chromatography (ethylacetate/n-hexane/methylene chloride=1/1/1-3/2/2). To the obtained solid,diisopropyl ether (20 mL) and ethyl acetate (10 mL) were added, and thesuspension was stirred at room temperature for overnight. Theprecipitated solid was collected by filtration, washed with a mixedsolvent of diisopropyl ether/ethyl acetate=2/1, and then dried to obtainthe title compound (4.18 g, yield: 64%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.34 (1H, d, J=2.7 Hz), 9.20 (1H, d,J=2.7 Hz), 7.34-7.32 (1H, m), 6.50-6.48 (2H, m), 4.76 (2H, s), 4.53-4.51(2H, m), 3.84 (3H, s), 3.81 (3H, s), 3.78-3.76 (2H, m).

(8d)7-Amino-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

A mixture of4-(2,4-dimethoxybenzyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(4.18 g, 11.6 mmol) obtained in Example (8c) and 10% palladium carbon(water content: 54.6%, 1.36 g) in tetrahydrofuran (110 mL) and ethanol(55 mL) was stirred at room temperature for 3 hours at normal pressureunder the hydrogen atmosphere. Hydrogen in the reaction container wasreplaced with nitrogen, and then, the reaction mixture was filteredthrough pad of Celite 545(R). The solvent in the filtrate was distilledoff under reduced pressure to obtain the title compound (3.93 g, yield:quantitative).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.86 (1H, d, J=3.1 Hz), 7.62 (1H, d,J=3.1 Hz), 7.31-7.28 (1H, m), 6.49-6.47 (2H, m), 4.75 (2H, s), 4.25 (2H,t, J=4.9 Hz), 3.82 (3H, s), 3.81 (3H, s), 3.64 (2H, br s), 3.55 (2H, t,J=4.9 Hz).

(8e)5-Chloro-N-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

To a mixture of7-amino-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(229 mg, 0.70 mmol) obtained in Example (8d) and pyridine (3.0 mL, 37.3mmol), 5-chloro-2-methoxybenzenesulfonyl chloride (190 mg, 0.79 mmol)was added at room temperature, and the mixture was stirred at 80° C. for2.5 hours in an oil bath. The reaction mixture was cooled and thenconcentrated under reduced pressure, and the residue was purified in anautomatic chromatography apparatus (ethyl acetate/methanol=100/0-85/15)to obtain the title compound (349 mg, yield: 94%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.24 (1H, d, J=3.0 Hz), 8.07 (1H, d,J=3.0 Hz), 7.74 (1H, d, J=2.4 Hz), 7.48 (1H, dd, J=8.8, 2.7 Hz),7.30-7.22 (2H, m), 7.01 (1H, d, J=9.1 Hz), 6.49-6.46 (2H, m), 4.70 (2H,s), 4.32 (2H, t, J=4.6 Hz), 4.09 (3H, s), 3.81-3.80 (6H, m), 3.60 (2H,t, J=4.6 Hz).

MS spectrum (ES/APCI⁺): 534 (M+H), 536 (M+2+H).

(Example 9)5-Chloro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

To a suspension of5-chloro-N-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide(335 mg, 0.63 mmol) obtained in Example (8e) in chloroform (5 mL),anisole (0.136 mL, 1.25 mmol), trifluoroacetic acid (2 mL, 26 mmol) andtrifluoromethanesulfonic acid (0.165 mL, 1.88 mmol) were added at roomtemperature, and the mixture was stirred at room temperature for 1 hour.The reaction mixture was concentrated under reduced pressure, and theconcentrated mixture was diluted by addition of chloroform and asaturated aqueous solution of sodium bicarbonate and stirred at roomtemperature for 10 minutes. The organic layer was separated, and theaqueous layer was subjected to extraction with a mixed solvent of ethylacetate/tetrahydrofuran=2/1 three times. All the organic layers werecombined and dried over anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure. To the residue, ethylacetate was added, and the precipitated solid was collected byfiltration to obtain the title compound (154 mg, yield: 64%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.29 (1H, s), 8.53 (1H, br t,J=5.2 Hz), 8.11-8.08 (2H, m), 7.69-7.64 (2H, m), 7.26 (1H, d, J=8.5 Hz),4.37-4.35 (2H, m), 3.88 (3H, s), 3.38-3.34 (2H, m).

MS spectrum (ES/APCI⁺): 384 (M+H), 386 (M+2+H).

(Example 10)5-Fluoro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

(10a)N-[4-(2,4-Dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide

To a mixture of7-amino-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(200 mg, 0.61 mmol) obtained in Example (8d) and pyridine (6 mL, 74.6mmol), 5-fluoro-2-methoxybenzenesulfonyl chloride (158 mg, 0.70 mmol)was added at room temperature, and the mixture was stirred at 80° C. for2 hours in an oil bath. The reaction mixture was cooled and thenconcentrated under reduced pressure, and the residue was purified in anautomatic chromatography apparatus (ethyl acetate/methanol=100/0-90/10)to obtain the title compound (305 mg, yield: 97%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.24 (1H, d, J=2.4 Hz), 8.08 (1H, d,J=2.4 Hz), 7.52-7.49 (1H, m), 7.26-7.20 (2H, m), 7.04-7.00 (1H, m), 6.95(1H, br s), 6.48-6.46 (2H, m), 4.70 (2H, s), 4.31 (2H, br t, J=4.3 Hz),4.08 (3H, s), 3.81-3.80 (6H, m), 3.59 (2H, br t, J=4.3 Hz).

(10b)5-Fluoro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

To a suspension ofN-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide(305 mg, 0.59 mmol) obtained in Example (10a) in chloroform (5 mL),anisole (0.128 mL, 1.17 mmol), trifluoroacetic acid (2 mL, 26 mmol) andtrifluoromethanesulfonic acid (0.155 mL, 1.77 mmol) were added at roomtemperature, and the mixture was stirred at room temperature for 1 hour.The reaction mixture was concentrated under reduced pressure, and theconcentrated mixture was diluted by addition of ethyl acetate and asaturated aqueous solution of sodium bicarbonate and stirred at roomtemperature for 1.5 hours. The precipitated solid was collected byfiltration to obtain the title compound (192 mg, yield: 89%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.28 (1H, s), 8.52 (1H, br t,J=4.9 Hz), 8.11-8.08 (2H, m), 7.51-7.46 (2H, m), 7.26-7.23 (1H, m), 4.36(2H, t, J=4.3 Hz), 3.86 (3H, s), 3.40-3.35 (2H, m).

MS spectrum (ES/APCI⁺): 368 (M+H).

(Example 11)2,5-Dimethoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

(11a)N-[4-(2,4-Dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2,5-dimethoxybenzenesulfonamide

To a mixture of7-amino-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(200 mg, 0.61 mmol) obtained in Example (8d) and pyridine (5 mL, 62mmol), 2,5-dimethoxybenzenesulfonyl chloride (158 mg, 0.67 mmol) wasadded, and the mixture was stirred at 80° C. for 3 hours in an oil bath.The reaction mixture was cooled and then concentrated under reducedpressure, and the residue was purified in an automatic chromatographyapparatus (ethyl acetate/methanol=100/0-85/15) to obtain the titlecompound (290 mg, yield: 90%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.24 (1H, d, J=3.0 Hz), 8.09-8.08(1H, m), 7.30-7.25 (2H, m), 7.07-6.98 (3H, m), 6.48-6.45 (2H, m), 4.70(2H, s), 4.30 (2H, t, J=4.6 Hz), 4.04 (3H, s), 3.81-3.79 (6H, m), 3.75(3H, s), 3.58 (2H, t, J=4.6 Hz).

(11b)2,5-Dimethoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

To a solution ofN-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2,5-dimethoxybenzenesulfonamide(290 mg, 0.55 mmol) obtained in Example (11a) in chloroform (4 mL),anisole (0.12 mL, 1.1 mmol), trifluoroacetic acid (2 mL, 26 mmol) andtrifluoromethanesulfonic acid (0.15 mL, 1.7 mmol) were added, and themixture was stirred at room temperature for 1 hour. The reaction mixturewas neutralized by the addition of a saturated aqueous solution ofsodium bicarbonate, followed by extraction with chloroform. The organiclayer was dried over anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure. To the residue,diisopropyl ether was added, and the precipitated solid was collected byfiltration, washed with diisopropyl ether, and then dried to obtain thetitle compound (144 mg, yield: 77%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.16 (1H, s), 8.51 (1H, t, J=5.2Hz), 8.09 (2H, dd, J=10.3, 3.0 Hz), 7.21-7.12 (3H, m), 4.35 (2H, t,J=4.3 Hz), 3.81 (3H, s), 3.72 (3H, s), 3.39-3.34 (2H, m).

MS spectrum (ES/APCI⁺): 380 (M+H).

(Example 12)2-Methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

(12a)N-[4-(2,4-Dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

To a mixture of7-amino-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(150 mg, 0.46 mmol) obtained in Example (8d) and pyridine (4 mL, 50mmol), 2-methoxybenzenesulfonyl chloride (104 mg, 0.50 mmol) was added,and the mixture was stirred at 80° C. for 2.5 hours in an oil bath. Thereaction mixture was cooled and then concentrated under reducedpressure, and the residue was purified in an automatic chromatographyapparatus (ethyl acetate/methanol=100/0-85/15) to obtain the titlecompound (212 mg, yield: 93%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.23 (1H, d, J=2.4 Hz), 8.07-8.06(1H, m), 7.79-7.77 (1H, m), 7.55-7.51 (1H, m), 7.30-7.24 (1H, m),7.08-6.98 (2H, m), 6.92 (1H, s), 6.48-6.43 (2H, m), 4.69 (2H, s), 4.29(2H, t, J=4.3 Hz), 4.09 (3H, s), 3.81-3.78 (6H, m), 3.56 (2H, t, J=4.6Hz).

(12b)2-Methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

To a suspension ofN-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide(212 mg, 0.43 mmol) obtained in Example (12a) in chloroform (4 mL),anisole (0.1 mL, 0.9 mmol), trifluoroacetic acid (2 mL, 26 mmol) andtrifluoromethanesulfonic acid (0.11 mL, 1.3 mmol) were added, and themixture was stirred at room temperature for 3 hours. The reactionmixture was neutralized by the addition of a saturated aqueous solutionof sodium bicarbonate, followed by extraction with chloroform twice. Theorganic layer was dried over anhydrous sodium sulfate. After filtration,the solvent was distilled off under reduced pressure. To the residue,diisopropyl ether was added, and the precipitated solid was collected byfiltration, washed with diisopropyl ether, and then dried to obtain thetitle compound (55.2 mg, yield: 37%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.12 (1H, s), 8.52-8.48 (1H, m),8.10-8.06 (2H, m), 7.70 (1H, dd, J=7.9, 1.8 Hz), 7.61-7.56 (1H, m), 7.20(1H, d, J=8.5 Hz), 7.03 (1H, t, J=7.6 Hz), 4.34 (2H, t, J=4.3 Hz), 3.88(3H, s), 3.37-3.31 (2H, m).

MS spectrum (ES/APCI⁺): 350 (M+H).

(Example 13)5-Chloro-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-(trifluoromethoxy)benzenesulfonamide

(13a) 5-Chloro-2-(trifluoromethoxy)benzenesulfonyl chloride

To chlorosulfonic acid (30.0 mL, 451 mmol), 4-chlorophenyltrifluoromethyl ether (2.60 mL, 18.1 mmol) was added, and the mixturewas stirred at room temperature for 46 hours. The reaction mixture wascarefully poured into ice (approximately 300 mL), followed by extractionwith methylene chloride twice. The organic layer was washed with waterand a saturated aqueous solution of sodium chloride and dried overanhydrous magnesium sulfate. After filtration, the solvent was distilledoff under reduced pressure, and the residue was purified by silica gelcolumn chromatography (n-hexane/methylene chloride=1/1) to obtain thetitle compound (approximately 83% content, 4.67 g, yield: 73%) as amixture containing positional isomers.

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.09 (0.83H, d, J=2.7 Hz), 8.02(0.17H, br d, J=2.7 Hz), 7.75 (0.83H, dd, J=8.8, 2.7 Hz), 7.71 (0.17H,d, J=8.6 Hz), 7.55-7.52 (0.17H, m), 7.50-7.47 (0.83H, m).

(13b)5-Chloro-N-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-(trifluoromethoxy)benzenesulfonamide

To a mixture of7-amino-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(260 mg, 0.79 mmol) obtained in Example (8d) and pyridine (8 mL, 99mmol), 5-chloro-2-(trifluoromethoxy)benzenesulfonyl chloride(approximately 83% content, 325 mg, 0.92 mmol) obtained in Example (13a)was added at room temperature, and the mixture was stirred at 80° C. for2.5 hours in an oil bath. The reaction mixture was cooled and thenconcentrated under reduced pressure, and the residue was purified in anautomatic chromatography apparatus (n-hexane/ethyl acetate=100/0-0/100)to obtain the title compound (305 mg, yield: 66%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.29 (1H, d, J=3.0 Hz), 8.17 (1H, d,J=3.0 Hz), 7.90 (1H, d, J=3.0 Hz), 7.58-7.54 (1H, m), 7.38-7.27 (3H, m),6.49-6.44 (2H, m), 4.73 (2H, s), 4.33 (2H, t, J=4.6 Hz), 3.81 (6H, s),3.63-3.60 (2H, m).

(13c)5-Chloro-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-(trifluoromethoxy)benzenesulfonamide

To a solution of5-chloro-N-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-(trifluoromethoxy)benzenesulfonamide(305 mg, 0.52 mmol) obtained in Example (13b) and anisole (0.113 mL,1.04 mmol) in chloroform (8 mL), trifluoroacetic acid (3 mL, 39 mmol)and trifluoromethanesulfonic acid (0.137 mL, 1.56 mmol) were added atroom temperature, and the mixture was stirred at room temperature for2.5 hours. To the reaction mixture, water was added, and the mixture wasstirred at room temperature for 1 hour, followed by extraction withethyl acetate. The organic layer was washed with a saturated aqueoussolution of sodium bicarbonate and dried over anhydrous sodium sulfate.After filtration, the solvent was distilled off under reduced pressure.To the residue, diisopropyl ether was added, and the precipitated solidwas collected by filtration, washed with diisopropyl ether, and thendried to obtain the title compound (171 mg, yield: 75%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.78 (1H, s), 8.58-8.53 (1H, m),8.13-8.06 (2H, m), 7.91-7.85 (2H, m), 7.65-7.60 (1H, m), 4.39 (2H, t,J=4.3 Hz), 3.41-3.36 (2H, m).

MS spectrum (ES/APCI⁺): 438 (M+H), 440 (M+2+H).

(Example 14)5-Chloro-N-(2,4-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-methoxybenzenesulfonamide

(14a)2,4-Dimethyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (280 mg, yield for 2 steps: 44%) was obtained byproduction according to Examples (1a) and (1b) using2-chloro-5-nitropyridine-3-carboxylic acid (550 mg, 2.71 mmol) and1-(methylamino)propan-2-ol (240 mg, 2.69 mmol) as starting materials.

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.23 (2H, s), 4.92-4.85 (1H, m),3.69-3.56 (2H, m), 3.27 (3H, s), 1.24 (3H, d, J=12.8 Hz).

(14b)7-Amino-2,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (200 mg, yield: 82%) was obtained by productionaccording to the method described in Example (1c) using2,4-dimethyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(280 mg, 1.18 mmol) obtained in Example (14a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.87 (1H, d, J=3.0 Hz), 7.50 (1H, d,J=3.0 Hz), 4.77-4.70 (1H, m), 4.00-3.91 (1H, m), 3.65 (2H, br s),3.49-3.44 (1H, m), 3.35-3.27 (1H, m), 3.23 (3H, s), 1.43 (5H, d, J=6.7Hz).

(14c)5-Chloro-N-(2,4-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-methoxybenzenesulfonamide

The title compound (90 mg, yield: 46%) was obtained by productionaccording to Example (1d) using7-amino-2,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (99mg, 0.48 mmol) obtained in Example (14b) and5-chloro-2-methoxybenzenesulfonyl chloride (132.5 mg, 0.55 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.39 (1H, s), 8.08 (1H, d, J=3.0Hz), 7.82 (1H, d, J=3.0 Hz), 7.69-7.66 (2H, m), 7.28-7.23 (1H, m),4.73-4.67 (1H, m), 3.86 (3H, s), 3.55-3.49 (1H, m), 3.40-3.29 (2H, m),3.07 (3H, s), 1.26 (4H, d, J=6.1 Hz).

MS spectrum (ES/APCI⁺): 412 (M+H), 414 (M+2+H).

(Example 15)N-(2,4-Dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-5-fluoro-2-methoxybenzenesulfonamide

The title compound (104 mg, yield: 55%) was obtained by productionaccording to Example (1d) using7-amino-2,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (99mg, 0.48 mmol) obtained in Example (14b) and5-fluoro-2-methoxybenzenesulfonyl chloride (114 mg, 0.51 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.38 (1H, s), 8.08 (1H, d, J=2.4Hz), 7.82-7.81 (1H, m), 7.53-7.47 (2H, m), 7.24 (1H, dd, J=8.5, 4.3 Hz),4.72-4.67 (1H, m), 3.85 (3H, s), 3.54-3.48 (1H, m), 3.39-3.30 (1H, m),3.07 (3H, s), 1.25 (3H, d, J=6.1 Hz).

MS spectrum (ES/APCI⁺): 396 (M+H).

(Example 16)5-Chloro-N-(3,4-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-methoxybenzenesulfonamide

(16a)3,4-Dimethyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (234 mg, yield for 2 steps: 37%) was obtained byproduction according to the method described in Examples (1a) and (1b)using 2-chloro-5-nitropyridine-3-carboxylic acid (550 mg, 2.71 mmol) and2-(methylamino)propan-1-ol (240 mg, 2.69 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.59 (1H, d, J=3.0 Hz), 9.23-9.20(1H, m), 4.70 (1H, dd, J=13.1, 5.2 Hz), 4.47 (1H, d, J=12.8 Hz),3.84-3.76 (1H, m), 3.25 (3H, s), 1.36 (4H, d, J=7.3 Hz).

(16b)7-Amino-3,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (168 mg, yield: 82%) was obtained by productionaccording to the method described in Example (1c) using3,4-dimethyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(234 mg, 0.99 mmol) obtained in Example (16a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.00 (1H, d, J=3.0 Hz), 7.88 (1H, d,J=3.0 Hz), 4.44 (1H, dd, J=12.5, 6.4 Hz), 4.28-4.23 (1H, m), 3.81-3.71(1H, m), 3.60 (2H, br s), 3.18 (3H, s), 1.32 (3H, d, J=6.7 Hz).

(16c)5-Chloro-N-(3,4-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-methoxybenzenesulfonamide

The title compound (73 mg, yield: 44%) was obtained by productionaccording to Example (1d) using7-amino-3,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (84mg, 0.41 mmol) obtained in Example (16b) and5-chloro-2-methoxybenzenesulfonyl chloride (111 mg, 0.46 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.36-8.32 (2H, m), 7.74 (1H, d,J=3.1 Hz), 7.46 (1H, dd, J=8.9, 2.7 Hz), 7.06 (1H, br s), 7.00 (1H, d,J=8.5 Hz), 4.51 (1H, dd, J=12.8, 5.5 Hz), 4.26 (1H, d, J=12.8 Hz), 4.08(3H, s), 3.73-3.67 (1H, m), 3.17 (3H, s), 1.30 (3H, d, J=6.7 Hz).

MS spectrum (ES/APCI⁺): 412 (M+H), 414 (M+2+H).

(Example 17)N-(3,4-Dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-5-fluoro-2-methoxybenzenesulfonamide

The title compound (78 mg, yield: 50%) was obtained by productionaccording to Example (1d) using7-amino-3,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (83mg, 0.40 mmol) obtained in Example (16b) and5-fluoro-2-methoxybenzenesulfonyl chloride (104 mg, 0.46 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.36-8.31 (2H, m), 7.49 (1H, dd,J=7.6, 3.4 Hz), 7.24-7.20 (1H, m), 7.08 (1H, br s), 7.02 (1H, dd, J=9.2,4.3 Hz), 4.51 (1H, dd, J=12.5, 5.2 Hz), 4.25 (1H, d, J=12.8 Hz), 4.08(3H, s), 3.73-3.66 (1H, m), 3.16 (3H, s), 1.29 (3H, d, J=7.3 Hz).

MS spectrum (ES/APCI⁺): 396 (M+H).

(Example 18)5-Chloro-N-[(3S)-3,4-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

(18a) (2S)-2-[(2,4-Dimethoxybenzyl)amino]propan-1-ol

The title compound (2.98 g, yield: 99%) was obtained by productionaccording to the method described in Example (8a) using2,4-dimethoxybenzaldehyde (2.22 g, 13.4 mmol) and(2S)-2-aminopropan-1-ol (1 g, 13.3 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.13 (1H, d, J=7.9 Hz), 6.50-6.42(2H, m), 3.85-3.79 (7H, m), 3.77-3.60 (3H, m), 3.26 (1H, dd, J=10.6, 6.4Hz), 2.84-2.76 (1H, m), 1.06 (3H, d, J=6.7 Hz).

(18b)(3S)-4-(2,4-Dimethoxybenzyl)-3-methyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (781.8 mg, yield for 2 steps: 60%) was obtained byproduction according to the method described in Examples (1a) and (1b)using 2-chloro-5-nitropyridine-3-carboxylic acid (700 mg, 3.46 mmol) and(2S)-2-[(2,4-dimethoxybenzyl)amino]propan-1-ol (785 mg, 3.49 mmol)obtained in Example (18a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.62-9.61 (1H, m), 9.20 (1H, d,J=3.0 Hz), 7.33 (1H, d, J=8.5 Hz), 6.50-6.47 (2H, m), 4.95 (1H, d,J=14.6 Hz), 4.65-4.55 (2H, m), 4.31 (1H, d, J=12.8 Hz), 4.04-3.97 (1H,m), 3.84 (3H, s), 3.81 (3H, s), 1.23 (3H, d, J=6.7 Hz).

(18c)(3S)-3-Methyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

To a solution of(3S)-4-(2,4-dimethoxybenzyl)-3-methyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(450 mg, 1.21 mmol) obtained in Example (18b) and anisole (0.2 mL, 1.8mmol) in chloroform (5 mL), trifluoroacetic acid (3 mL, 39 mmol) andtrifluoromethanesulfonic acid (0.2 mL, 2.3 mmol) were added, and themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, and the concentrated mixturewas diluted by addition of chloroform, washed with a saturated aqueoussolution of sodium bicarbonate and a saturated aqueous solution ofsodium chloride, and dried over anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure. To theresidue, diisopropyl ether was added, and the precipitated solid wascollected by filtration, washed with diisopropyl ether, and then driedto obtain the title compound (228 mg, yield: 85%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.49-9.47 (1H, m), 9.26-9.24 (1H,m), 6.49 (1H, br s), 4.60 (1H, d, J=12.1 Hz), 4.47-4.40 (1H, m),4.02-3.94 (1H, m), 1.42-1.39 (3H, m).

(18d)(3S)-3,4-Dimethyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

To a solution of(3S)-3-methyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(228 mg, 1.02 mmol) obtained in Example (18c) in N,N-dimethylformamide(5 mL), sodium hydride (63% content, 53 mg, 1.39 mmol) was added underice cooling, and the mixture was stirred at room temperature for 20minutes. Subsequently, the mixture was cooled in an ice water bath.Methyl iodide (0.127 mL, 2.04 mmol) was added thereto, and the mixturewas stirred at room temperature for 1 hour and 45 minutes. The reactionmixture was diluted by addition of ethyl acetate, washed with a 5%aqueous sodium chloride solution three times, and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (n-hexane/ethyl acetate=100/0-0/100) to obtainthe title compound (160 mg, yield: 66%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.59 (1H, d, J=3.0 Hz), 9.22-9.21(1H, m), 4.70 (1H, dd, J=12.8, 5.5 Hz), 4.47 (1H, d, J=12.8 Hz),3.84-3.77 (1H, m), 3.25 (3H, s), 1.36 (3H, d, J=7.3 Hz).

(18e)(3S)-7-Amino-3,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (175 mg, yield: quantitative) was obtained byproduction according to the method described in Example (3c) using(3S)-3,4-dimethyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(160 mg, 0.67 mmol) obtained in Example (18d).

¹H NMR spectrum (CD₃OD, 400 MHz) δ: 7.87-7.85 (1H, m), 7.79-7.78 (1H,m), 5.47-5.44 (1H, m), 4.45-4.39 (1H, m), 4.22 (1H, d, J=12.8 Hz),3.92-3.84 (2H, m), 3.15 (3H, s), 1.32-1.23 (3H, m).

(18f)5-Chloro-N-[(3S)-3,4-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

The title compound (87 mg, yield: 63%) was obtained by productionaccording to Example (1d) using(3S)-7-amino-3,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(69 mg, 0.34 mmol) obtained in Example (18e) and5-chloro-2-methoxybenzenesulfonyl chloride (91 mg, 0.38 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.34 (2H, dd, J=12.1, 2.4 Hz), 7.74(1H, d, J=2.4 Hz), 7.46 (1H, dd, J=8.8, 2.7 Hz), 7.10 (1H, s), 7.00 (1H,d, J=9.1 Hz), 4.51 (1H, dd, J=12.8, 5.5 Hz), 4.26 (1H, d, J=12.8 Hz),4.07 (3H, s), 3.74-3.66 (1H, m), 3.17 (3H, s), 1.30 (3H, d, J=7.3 Hz).

MS spectrum (ES/APCI⁺): 412 (M+H), 414 (M+2+H).

(Example 19)N-[(3S)-3,4-Dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide

The title compound (81 mg, yield: 61%) was obtained by productionaccording to Example (1d) using(3S)-7-amino-3,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(69 mg, 0.34 mmol) obtained in Example (18e) and5-fluoro-2-methoxybenzenesulfonyl chloride (88 mg, 0.39 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.34 (2H, dd, J=14.9, 2.7 Hz), 7.49(1H, dd, J=7.9, 3.0 Hz), 7.24-7.19 (1H, m), 7.08 (1H, s), 7.02 (1H, dd,J=9.1, 4.3 Hz), 4.51 (1H, dd, J=12.8, 5.5 Hz), 4.25 (1H, d, J=12.8 Hz),4.07 (3H, s), 3.73-3.66 (1H, m), 3.16 (3H, s), 1.29 (3H, d, J=6.7 Hz).

MS spectrum (ES/APCI⁺): 396 (M+H).

(Example 20)5-Chloro-N-[(3R)-3,4-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

(20a) (2R)-2-[(2,4-Dimethoxybenzyl)amino]propan-1-ol

The title compound (3.10 g, yield: quantitative) was obtained byproduction according to the method described in Example (8a) using2,4-dimethoxybenzaldehyde (2.25 g, 13.5 mmol) and(2R)-2-aminopropan-1-ol (1.02 g, 13.6 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.13 (1H, d, J=7.9 Hz), 6.50-6.42(2H, m), 3.86-3.79 (7H, m), 3.77-3.61 (3H, m), 3.26 (1H, dd, J=10.6, 6.4Hz), 2.84-2.76 (1H, m), 1.06 (3H, d, J=6.1 Hz).

(20b)(3R)-4-(2,4-Dimethoxybenzyl)-3-methyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (783 mg, yield for 2 steps: 61%) was obtained using2-chloro-5-nitropyridine-3-carboxylic acid (700 mg, 3.46 mmol) and(2R)-2-[(2,4-dimethoxybenzyl)amino]propan-1-ol (778 mg, 3.45 mmol)obtained in Example (20a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.62 (1H, d, J=3.0 Hz), 9.20 (1H, d,J=3.0 Hz), 7.33 (1H, d, J=8.5 Hz), 6.50-6.47 (2H, m), 4.95 (1H, d,J=14.0 Hz), 4.65-4.54 (2H, m), 4.31 (1H, d, J=13.4 Hz), 4.04-3.97 (1H,m), 3.84 (3H, s), 3.81 (3H, s), 1.23 (3H, d, J=7.3 Hz).

(20c)(3R)-3,4-Dimethyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (120 mg, yield for 2 steps: 48%) was obtained byproduction according to the method described in Examples (18c) and (18d)using(3R)-4-(2,4-dimethoxybenzyl)-3-methyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(390 mg, 1.04 mmol) obtained in Example (20b).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.59 (1H, d, J=2.4 Hz), 9.21 (1H, d,J=2.4 Hz), 4.70 (1H, dd, J=13.1, 5.2 Hz), 4.47 (1H, d, J=13.1 Hz),3.84-3.77 (1H, m), 3.25 (3H, s), 1.36 (3H, d, J=6.7 Hz).

(20d)(3R)-7-Amino-3,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (87.9 mg, yield: 84%) was obtained by productionaccording to the method described in Example (1c) using(3R)-3,4-dimethyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(120 mg, 0.51 mmol) obtained in Example (20c).

¹H NMR spectrum (CD₃OD, 400 MHz) δ: 7.86 (1H, d, J=3.0 Hz), 7.79 (1H, d,J=3.0 Hz), 4.42 (1H, dd, J=12.5, 7.0 Hz), 4.22 (1H, dd, J=12.5, 1.5 Hz),3.93-3.86 (1H, m), 3.15 (3H, s), 1.27 (3H, d, J=6.7 Hz).

(20e)5-Chloro-N-[(3R)-3,4-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

The title compound (82 mg, yield: 96%) was obtained by productionaccording to Example (1d) using(3R)-7-amino-3,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(43 mg, 0.21 mmol) obtained in Example (20d) and5-chloro-2-methoxybenzenesulfonyl chloride (58 mg, 0.24 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.33 (2H, dd, J=8.8, 2.7 Hz), 7.73(1H, d, J=3.0 Hz), 7.46 (1H, dd, J=8.8, 2.7 Hz), 7.02-6.97 (2H, m), 4.51(1H, dd, J=12.8, 5.5 Hz), 4.26 (1H, d, J=12.8 Hz), 4.09 (3H, s),3.73-3.67 (1H, m), 3.16 (3H, s), 1.30 (3H, d, J=6.7 Hz).

MS spectrum (ES/APCI⁺): 412 (M+H), 414 (M+2+H).

(Example 21)N-[(3R)-3,4-Dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide

The title compound (74 mg, yield: 90%) was obtained by productionaccording to Example (1d) using(3R)-7-amino-3,4-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(43 mg, 0.21 mmol) obtained in Example (20d) and5-fluoro-2-methoxybenzenesulfonyl chloride (56 mg, 0.25 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.33 (2H, dd, J=12.5, 2.7 Hz), 7.49(1H, dd, J=7.3, 3.0 Hz), 7.24-7.19 (1H, m), 7.04-7.00 (2H, m), 4.51 (1H,dd, J=12.8, 5.5 Hz), 4.25 (1H, d, J=12.8 Hz), 4.08 (3H, s), 3.72-3.66(1H, m), 3.16 (3H, s), 1.29 (3H, d, J=6.7 Hz).

MS spectrum (ES/APCI⁺): 396 (M+H).

(Example 22)5-Chloro-2-methoxy-N-[(3S)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

(22a)(3S)-7-Amino-4-(2,4-dimethoxybenzyl)-3-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

To a mixture of(3S)-4-(2,4-dimethoxybenzyl)-3-methyl-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(330 mg, 0.88 mmol) obtained in Example (18b) in tetrahydrofuran (4 mL)and methanol (4 mL), nickel(II) chloride hexahydrate (432 mg, 1.82 mmol)was added. Subsequently, the mixture was cooled in an ice water bath.Sodium borohydride (134 mg, 3.54 mmol) was added thereto over 10minutes, and then, the mixture was stirred at room temperature for 2hours. The reaction mixture was diluted by addition of acetone, thenCelite 545(R) (approximately 0.6 g) was added thereto, and the mixturewas stirred at room temperature for 1 hour. The reaction mixture wasfiltered, and the solvent in the filtrate was distilled off underreduced pressure to obtain the title compound (303 mg, yield:quantitative).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.10 (1H, d, J=3.0 Hz), 7.89 (1H, d,J=3.0 Hz), 7.31-7.26 (1H, m), 6.49-6.44 (2H, m), 4.93 (1H, d, J=14.6Hz), 4.57 (1H, d, J=14.6 Hz), 4.38 (1H, dd, J=12.8, 5.8 Hz), 4.12 (1H,d, J=12.8 Hz), 4.00-3.74 (7H, m), 3.57 (2H, br s), 1.21 (3H, d, J=7.3Hz).

(22b)5-Chloro-N-[(3S)-4-(2,4-dimethoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

To a mixture of(3S)-7-amino-4-(2,4-dimethoxybenzyl)-3-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(150 mg, 0.44 mmol) obtained in Example (22a) and pyridine (3 mL, 37mmol), 5-chloro-2-methoxybenzenesulfonyl chloride (121 mg, 0.50 mmol)was added, and the mixture was stirred at 80° C. for 1 hour in an oilbath. The reaction mixture was cooled and then concentrated underreduced pressure, and the residue was purified in an automaticchromatography apparatus (ethyl acetate/methanol=100/0-85/15) to obtainthe title compound (200 mg, yield: 83%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.38 (1H, d, J=2.4 Hz), 8.31 (1H, d,J=2.4 Hz), 7.74 (1H, d, J=2.4 Hz), 7.47 (1H, dd, J=9.1, 2.4 Hz), 7.21(1H, d, J=9.1 Hz), 7.01 (1H, d, J=9.1 Hz), 6.92 (1H, s), 6.47-6.43 (2H,m), 4.91 (1H, d, J=15.2 Hz), 4.51-4.41 (2H, m), 4.15-4.11 (1H, m), 4.09(3H, s), 3.85-3.80 (1H, m), 3.80-3.79 (6H, m), 1.17 (3H, d, J=6.7 Hz).

(22c)5-Chloro-2-methoxy-N-[(3S)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

To a solution of5-chloro-N-[(3S)-4-(2,4-dimethoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide(200 mg, 0.36 mmol) obtained in Example (22b) and anisole (0.1 mL, 0.9mmol) in chloroform (3 mL), trifluoroacetic acid (1 mL, 13 mmol) andtrifluoromethanesulfonic acid (0.1 mL, 1.1 mmol) were added, and themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, and then, the residue wasdiluted with chloroform, washed with a saturated aqueous solution ofsodium bicarbonate and a saturated aqueous solution of sodium chloride,and dried over anhydrous sodium sulfate. After filtration, the solventwas distilled off under reduced pressure. To the residue, diisopropylether was added, and the precipitated solid was collected by filtration,washed with diisopropyl ether, and then dried to obtain the titlecompound (105 mg, yield: 72%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.31 (1H, d, J=3.0 Hz), 8.22 (1H, d,J=2.4 Hz), 7.74 (1H, d, J=2.4 Hz), 7.47 (1H, dd, J=9.1, 2.4 Hz),7.02-6.95 (2H, m), 6.10 (1H, br s), 4.41 (1H, d, J=12.1 Hz), 4.23 (1H,dd, J=12.8, 7.3 Hz), 4.08 (3H, s), 1.31 (3H, d, J=6.7 Hz).

MS spectrum (ES/APCI⁺): 398 (M+H), 400 (M+2+H).

(Example 23)5-Fluoro-2-methoxy-N-[(3S)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

(23a)N-[(3S)-4-(2,4-Dimethoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide

To a mixture of(3S)-7-amino-4-(2,4-dimethoxybenzyl)-3-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(150 mg, 0.44 mmol) obtained in Example (22a) and pyridine (3 mL, 37mmol), 5-fluoro-2-methoxybenzenesulfonyl chloride (120 mg, 0.53 mmol)was added, and the mixture was stirred at 80° C. for 2 hours and 20minutes in an oil bath. The reaction mixture was cooled and thenconcentrated under reduced pressure, and the residue was purified in anautomatic chromatography apparatus (ethyl acetate/methanol=100/0-85/15)to obtain the title compound (189 mg, yield: 81%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.39 (1H, d, J=3.0 Hz), 8.30-8.29(1H, m), 7.50 (1H, dd, J=7.9, 3.0 Hz), 7.31-7.20 (2H, m), 7.03 (1H, dd,J=9.1, 3.6 Hz), 6.95 (1H, br s), 6.46-6.44 (2H, m), 4.91 (1H, d, J=14.6Hz), 4.49 (1H, d, J=14.6 Hz), 4.43 (1H, dd, J=12.8, 5.5 Hz), 4.16-4.11(1H, m), 4.09 (3H, s), 3.84-3.79 (7H, m), 1.16 (3H, d, J=6.7 Hz).

(23b)5-Fluoro-2-methoxy-N-[(3S)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

To a solution ofN-[(3S)-4-(2,4-dimethoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide(189 mg, 0.35 mmol) obtained in Example (23a) and anisole (0.1 mL, 0.9mmol) in chloroform (3 mL), trifluoroacetic acid (1 mL, 13 mmol) andtrifluoromethanesulfonic acid (0.1 mL, 1.1 mmol) were added, and themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, and then, the residue wasdiluted with chloroform, washed with a saturated aqueous solution ofsodium bicarbonate and a saturated aqueous solution of sodium chloride,and dried over anhydrous sodium sulfate. After filtration, the solventwas distilled off under reduced pressure. To the residue, diisopropylether was added, and the precipitated solid was collected by filtration,washed with diisopropyl ether, and then dried to obtain the titlecompound (73.1 mg, yield: 54%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.31 (1H, d, J=2.4 Hz), 8.23 (1H, d,J=2.4 Hz), 7.49 (1H, dd, J=7.6, 3.3 Hz), 7.25-7.20 (1H, m), 7.07-7.00(2H, m), 6.14 (1H, br s), 4.41 (1H, d, J=11.5 Hz), 4.22 (1H, dd, J=12.8,7.3 Hz), 4.07 (3H, s), 3.88-3.82 (1H, m), 1.30 (3H, d, J=7.3 Hz).

MS spectrum (ES/APCI⁺): 382 (M+H).

(Example 24)5-Chloro-N-[(3S)-3-ethyl-4-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

(24a) (2S)-2-[(2,4-Dimethoxybenzyl)amino]butan-1-ol

The title compound (2.54 g, yield: 97%) was obtained by productionaccording to the method described in Example (8a) using2,4-dimethoxybenzaldehyde (1.81 g, 10.9 mmol) and (2S)-2-aminobutan-1-ol(0.98 g, 11.0 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.12 (1H, d, J=8.5 Hz), 6.48-6.41(2H, m), 3.83 (3H, s), 3.80 (3H, s), 3.71 (2H, s), 3.66 (1H, dd, J=10.3,4.3 Hz), 3.31 (1H, dd, J=10.3, 6.1 Hz), 2.60-2.52 (1H, m), 1.54-1.38(2H, m), 0.90 (3H, t, J=7.3 Hz).

(24b)(3S)-7-Bromo-4-(2,4-dimethoxybenzyl)-3-ethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (379 mg, yield for 2 steps: 78%) was obtained byproduction according to the method described in Examples (1a) and (1b)using 5-bromo-2-chloropyridine-3-carboxylic acid (500 mg, 2.11 mmol) and(2S)-2-[(2,4-dimethoxybenzyl)amino]butan-1-ol (506 mg, 2.11 mmol)obtained in Example (24a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.90 (1H, d, J=2.4 Hz), 8.38 (1H, d,J=2.4 Hz), 7.34-7.31 (1H, m), 6.49-6.46 (2H, m), 5.08 (1H, d, J=14.6Hz), 4.62 (1H, dd, J=13.1, 5.2 Hz), 4.41 (1H, d, J=14.6 Hz), 4.11-4.09(1H, m), 3.83 (3H, s), 3.81 (3H, s), 3.69-3.63 (1H, m), 1.62-1.52 (2H,m), 1.00 (3H, t, J=7.3 Hz).

(24c)(3S)-7-Bromo-3-ethyl-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (85.1 mg, yield for 2 steps: 66%) was obtained byproduction according to the method described in Examples (18c) and (18d)using(3S)-7-bromo-4-(2,4-dimethoxybenzyl)-3-ethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(189 mg, 0.45 mmol) obtained in Example (24b).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.86 (1H, d, J=2.4 Hz), 8.39 (1H, d,J=2.4 Hz), 4.72 (1H, dd, J=13.1, 5.2 Hz), 4.30 (1H, d, J=12.8 Hz),3.48-3.41 (1H, m), 3.22 (3H, s), 1.72-1.64 (2H, m), 1.05 (3H, t, J=7.6Hz).

(24d)5-Chloro-N-[(3S)-3-ethyl-4-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

The title compound (63.2 mg, yield: 50%) was obtained by productionaccording to the method described in Example (5d) using(3S)-7-bromo-3-ethyl-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(85.1 mg, 0.30 mmol) obtained in Example (24c) and5-chloro-2-methoxybenzenesulfonamide (75.8 mg, 0.34 mmol) obtained inExample (5a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.39-8.31 (2H, m), 7.74 (1H, d,J=3.0 Hz), 7.46 (1H, dd, J=8.8, 2.7 Hz), 7.13 (1H, br s), 6.99 (1H, d,J=9.1 Hz), 4.67 (1H, dd, J=13.4, 5.5 Hz), 4.22 (1H, d, J=12.8 Hz), 4.07(3H, s), 3.43-3.37 (1H, m), 3.19 (3H, s), 1.70-1.60 (2H, m), 1.02 (3H,t, J=7.3 Hz).

MS spectrum (ES/APCI⁺): 426 (M+H), 428 (M+2+H).

(Example 25)5-Chloro-N-[(3S)-3-ethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

The title compound (133 mg, yield for 2 steps: 72%) was obtained byproduction according to the method described in Examples (5d) and (9)using(3S)-7-bromo-4-(2,4-dimethoxybenzyl)-3-ethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(189 mg, 0.45 mmol) obtained in Example (24b) and5-chloro-2-methoxybenzenesulfonamide (104 mg, 0.47 mmol) obtained inExample (5a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.31 (1H, d, J=2.4 Hz), 8.25 (1H, d,J=3.0 Hz), 7.75 (1H, d, J=3.0 Hz), 7.47 (1H, dd, J=9.1, 2.4 Hz),7.29-7.25 (1H, m), 7.00 (1H, d, J=9.1 Hz), 6.27 (1H, br s), 4.42 (1H, d,J=12.8 Hz), 4.33 (1H, dd, J=12.8, 6.7 Hz), 4.07 (3H, s), 3.59-3.53 (1H,m), 1.73-1.60 (2H, m), 1.05 (3H, t, J=7.3 Hz).

MS spectrum (ES/APCI⁺): 412 (M+H), 414 (M+2+H).

(Example 26)5-Chloro-2-methoxy-N-[(3S)-5-oxo-3-(propan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

(26a) (2S)-2-[(2,4-Dimethoxybenzyl)amino]-3-methylbutan-1-ol

The title compound (2.53 g, yield: 99%) was obtained by productionaccording to the method described in Examples (8a) using2,4-dimethoxybenzaldehyde (1.68 g, 10.9 mmol) and(2S)-2-amino-3-methylbutan-1-ol (1.04 g, 10.1 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.11 (1H, d, J=7.9 Hz), 6.50-6.42(2H, m), 3.88-3.81 (7H, m), 3.71 (2H, d, J=4.3 Hz), 3.65 (1H, dd,J=10.3, 4.3 Hz), 3.35 (1H, dd, J=10.3, 6.7 Hz), 2.40-2.35 (1H, m),1.84-1.73 (1H, m), 0.95 (3H, d, J=6.7 Hz), 0.89 (3H, d, J=6.7 Hz).

(26b)(3S)-7-Bromo-4-(2,4-dimethoxybenzyl)-3-(propan-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (1.43 g, yield for 2 steps: 77%) was obtained byproduction according to the method described in Examples (1a) and (1b)using 5-bromo-2-chloropyridine-3-carboxylic acid (1.00 g, 4.23 mmol) and(2S)-2-[(2,4-dimethoxybenzyl)amino]-3-methylbutan-1-ol (1.07 g, 4.22mmol) obtained in Example (26a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.84 (1H, d, J=2.4 Hz), 8.37 (1H, d,J=2.4 Hz), 7.38-7.35 (1H, m), 6.50-6.43 (2H, m), 5.33 (1H, d, J=14.0Hz), 4.66 (1H, dd, J=12.8, 5.5 Hz), 4.17-4.11 (1H, m), 4.00 (1H, d,J=12.8 Hz), 3.83 (3H, s), 3.81 (3H, s), 3.40 (1H, dd, J=10.9, 5.5 Hz),1.85-1.78 (1H, m), 1.05 (3H, d, J=6.7 Hz), 1.02 (3H, d, J=6.7 Hz).

(26c)5-Chloro-2-methoxy-N-[(3S)-5-oxo-3-(propan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

The title compound (186 mg, yield for 2 steps: 53%) was obtained byproduction according to the method described in Examples (5d) and (9)using(3S)-7-bromo-4-(2,4-dimethoxybenzyl)-3-(propan-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(355 mg, 0.82 mmol) obtained in Example (26b) and5-chloro-2-methoxybenzenesulfonamide (199 mg, 0.90 mmol) obtained inExample (5a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.29 (2H, dd, J=16.4, 3.0 Hz), 7.75(1H, d, J=2.4 Hz), 7.47 (1H, dd, J=8.8, 2.7 Hz), 7.10 (1H, s), 7.00 (1H,d, J=8.5 Hz), 6.36-6.33 (1H, m), 4.47-4.39 (2H, m), 4.07 (3H, s),3.35-3.29 (1H, m), 1.95-1.88 (1H, m), 1.08-1.00 (6H, m).

MS spectrum (ES/APCI⁺): 426 (M+H), 428 (M+2+H).

(Example 27)5-Chloro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

(27a) (2R)-3-(Benzyloxy)-2-[(2,4-dimethoxybenzyl)amino]propan-1-ol

The title compound (4.18 g, yield: quantitative) was obtained byproduction according to the method described in Example (8a) using2,4-dimethoxybenzaldehyde (2.00 g, 12.0 mmol) and(2R)-2-amino-3-(benzyloxy)propan-1-ol (2.18 g, 12.0 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.36-2.26 (5H, m), 7.12 (1H, d,J=7.8 Hz), 6.45-6.42 (2H, m), 4.46 (2H, s), 3.81-3.68 (9H, m), 3.52 (2H,d, J=5.9 Hz), 3.44 (1H, dd, J=11.0, 4.3 Hz), 2.95-2.90 (1H, m).

(27b)N-[(2R)-1-(Benzyloxy)-3-hydroxypropan-2-yl]-2-chloro-N-(2,4-dimethoxybenzyl)-5-nitropyridine-3-carboxamide

To a suspension of 2-chloro-5-nitropyridine-3-carboxylic acid (1.21 g,5.97 mmol) in methylene chloride (30 mL), oxalyl chloride (0.64 mL, 7.5mmol) and N,N-dimethylformamide (0.024 mL, 0.31 mmol) were added at roomtemperature, and the mixture was stirred at the same temperature asabove for 30 minutes. The reaction mixture was concentrated underreduced pressure to prepare a crude product of2-chloro-5-nitropyridine-3-carboxylic acid chloride. To a solution of(2R)-3-(benzyloxy)-2-[(2,4-dimethoxybenzyl)amino]propan-1-ol (1.98 g,5.97 mmol) obtained in Example (27a) and N,N-diisopropylethylamine (2.05mL, 12.1 mmol) in tetrahydrofuran (15 mL), a solution of the crudeproduct of 2-chloro-5-nitropyridine-3-carboxylic acid chloride intetrahydrofuran (15 mL) was added over 10 minutes under ice cooling, andthe mixture was stirred at the same temperature as above for 10 minutes.To the reaction mixture, water (0.05 mL) was added, and then, themixture was concentrated under reduced pressure. The concentratedmixture was diluted by addition of water, followed by extraction withethyl acetate. The organic layer was washed with water and a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. After filtration, the solvent was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate=3/2-2/3) to obtain the titlecompound (2.74 g, yield: 89%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.21-9.18 (1H, m), 8.59-8.25 (1H,m), 7.58-6.98 (6H, m), 6.54-6.30 (2H, m), 4.97-2.83 (14H, m).

(27c)(3S)-3-[(Benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (ca.1.9 mol/L, 4.2 mL, 8.0 mmol) was diluted with tetrahydrofuran (130 mL).A solution ofN-[(2R)-1-(benzyloxy)-3-hydroxypropan-2-yl]-2-chloro-N-(2,4-dimethoxybenzyl)-5-nitropyridine-3-carboxamide(2.73 g, 5.29 mmol) obtained in Example (27b) in tetrahydrofuran (130mL) was added thereto over 40 minutes under ice cooling, and the mixturewas stirred at the same temperature as above for 10 minutes and furtherstirred at room temperature for 40 minutes. To the reaction mixture, asaturated aqueous solution of ammonium chloride (50 mL) was added, andthen, the mixture was concentrated into approximately ⅕ of the amountunder reduced pressure. The concentrated mixture was diluted by additionof water, followed by extraction with ethyl acetate twice. The organiclayer was washed with water and a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After filtration,the solvent was distilled off under reduced pressure, and the residuewas purified by silica gel column chromatography (n-hexane/ethylacetate=1/1) to obtain the title compound (1.93 g, yield: 76%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.53 (1H, d, J=3.1 Hz), 9.12 (1H, d,J=3.1 Hz), 7.35-7.19 (6H, m), 6.49-6.46 (2H, m), 5.06 (1H, d, J=14.1Hz), 4.88 (1H, dd, J=12.9, 5.1 Hz), 4.52 (1H, d, J=14.1 Hz), 4.46 (1H,d, J=11.7 Hz), 4.40 (1H, d, J=11.7 Hz), 4.26 (1H, d, J=12.9 Hz),4.16-4.10 (1H, m), 3.83 (6H, s) 3.56 (1H, dd, J=9.4, 7.4 Hz), 3.48 (1H,dd, J=9.4, 6.1 Hz).

(27d) (3S)-7-Amino-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

A mixture of(3S)-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(1.93 g, 4.03 mmol) obtained in Example (27c) and 10% palladium carbon(water content: 54.6%, 0.48 g) in tetrahydrofuran (26 mL) and ethanol(13 mL) was stirred at room temperature for 5 hours at normal pressureunder the hydrogen atmosphere. Hydrogen in the reaction container wasreplaced with nitrogen, and then, the reaction mixture was filteredthrough pad of Celite 545(R). The solvent in the filtrate was distilledoff under reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/methanol=1/0-20/1) to obtain thetitle compound (1.57 g, yield: 87%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.09 (1H, d, J=3.1 Hz), 7.87 (1H, d,J=3.1 Hz), 7.35-7.26 (6H, m), 6.46-6.44 (2H, m), 5.09 (1H, d, J=14.9Hz), 4.67 (1H, dd, J=12.7, 5.3 Hz), 4.53-4.42 (3H, m), 4.08-3.97 (2H,m), 3.80 (6H, s), 3.63 (1H, dd, J=9.6, 7.2 Hz), 3.56-3.47 (3H, m).

(27e)N-[(3S)-3-[(Benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-chloro-2-methoxybenzenesulfonamide

To a mixture of(3S)-7-amino-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(226 mg, 0.50 mmol) obtained in Example (27d) and pyridine (0.81 mL,37.3 mmol), 5-chloro-2-methoxybenzenesulfonyl chloride (134 mg, 0.55mmol) was added, and the mixture was stirred at 80° C. for 30 minutes inan oil bath. The reaction mixture was cooled and then concentrated underreduced pressure, and the concentrated mixture was diluted by additionof water, followed by extraction with ethyl acetate. The organic layerwas washed with water and a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After filtration,the solvent was distilled off under reduced pressure, and the residuewas purified by silica gel column chromatography (ethyl acetate) toobtain the title compound (323 mg, yield: 98%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.36 (1H, d, J=2.7 Hz), 8.30 (1H, d,J=2.7 Hz), 7.74 (1H, d, J=2.7 Hz), 7.46 (1H, dd, J=9.0, 2.7 Hz),7.34-7.21 (6H, m), 7.00 (1H, d, J=9.0 Hz), 6.90 (1H, br s), 6.45-6.43(2H, m), 5.04 (1H, d, J=14.5 Hz), 4.73 (1H, dd, J=12.9, 5.1 Hz),4.49-4.39 (3H, m), 4.08-4.05 (4H, m), 4.01-3.97 (1H, m), 3.79 (3H, s),3.77 (3H, s), 3.55 (1H, dd, J=9.6, 7.6 Hz), 3.43 (1H, dd, J=9.6, 6.5Hz).

(27f)5-Chloro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

To a solution ofN-[(3S)-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-chloro-2-methoxybenzenesulfonamide(324 mg, 0.50 mmol) obtained in Example (27e) and anisole (0.17 mL, 1.6mmol) in chloroform (2.5 mL), trifluoroacetic acid (0.76 mL, 9.9 mmol)and trifluoromethanesulfonic acid (0.13 mL, 1.5 mmol) were added, andthe mixture was stirred at room temperature for 3 hours. The reactionmixture was poured into a mixture of sodium bicarbonate (0.83 g, 9.9mmol) and water (5 mL), and the mixture was stirred at room temperaturefor 30 minutes. To the reaction mixture, sodium bicarbonate (0.13 g, 1.5mmol) was further added, and then, the mixture was concentrated underreduced pressure. The concentrated mixture was diluted by addition oftetrahydrofuran (5 mL). 2 N sulfuric acid (0.50 mL, 1.0 mmol) was addedthereto, and the mixture was stirred at room temperature for 10 minutes.To the reaction mixture, a 2 N aqueous sodium hydroxide solution (0.50mL, 1.0 mmol) was added, and the mixture was concentrated under reducedpressure. To the concentrated mixture, a saturated aqueous solution ofsodium chloride was added, and the mixture was washed with ethylacetate. The aqueous layer was rendered acidic by the addition of 1 Nhydrochloric acid, followed by extraction with a mixed solvent ofchloroform/isopropanol=3/1 twice. The organic layer was dried overanhydrous magnesium sulfate. After filtration, the solvent was distilledoff under reduced pressure. To the residue, ethyl acetate was added, andthe precipitated solid was collected by filtration, washed with ethylacetate, and then dried to obtain the title compound (162 mg, yield:79%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.29 (1H, br s), 8.35 (1H, br d,J=4.3 Hz), 8.24 (1H, d, J=3.1 Hz), 8.07 (1H, d, J=3.1 Hz), 7.68-7.64(2H, m), 7.25 (1H, d, J=9.0 Hz), 5.04 (1H, t, J=5.5 Hz), 4.40-4.32 (2H,m), 3.87 (3H, s), 3.48-3.36 (3H, m).

MS spectrum (ES/APCI): 412 (M−H), 414 (M+2-H).

(Example 28)5-Fluoro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

(28a)N-[(3S)-3-[(Benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide

To a mixture of(3S)-7-amino-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(310 mg, 0.69 mmol) obtained in Example (27d) and pyridine (1.1 mL, 13.7mmol), 5-fluoro-2-methoxybenzenesulfonyl chloride (171 mg, 0.76 mmol)was added, and the mixture was stirred at 80° C. for 30 minutes in anoil bath. The reaction mixture was cooled and then concentrated underreduced pressure, and the concentrated mixture was diluted by additionof water, followed by extraction with ethyl acetate. The organic layerwas washed with water and a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After filtration,the solvent was distilled off under reduced pressure, and the residuewas purified by silica gel column chromatography (ethyl acetate) toobtain the title compound (425 mg, yield: 97%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.37 (1H, d, J=2.7 Hz), 8.29 (1H, d,J=2.7 Hz), 7.49 (1H, dd, J=7.4, 3.1 Hz), 7.34-7.19 (7H, m), 7.02 (1H,dd, J=9.0, 3.9 Hz), 6.97 (1H, br s), 6.45-6.42 (2H, m), 5.03 (1H, d,J=14.5 Hz), 4.72 (1H, dd, J=12.7, 5.3 Hz), 4.48-4.39 (3H, m), 4.07-3.96(5H, m), 3.79 (3H, s), 3.77 (3H, s), 3.54 (1H, dd, J=9.6, 7.4 Hz), 3.42(1H, dd, J=9.6, 6.5 Hz).

(28b)5-Fluoro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

To a solution ofN-[(3S)-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide(213 mg, 0.33 mmol) obtained in Example (28a) and anisole (0.11 mL, 1.0mmol) in chloroform (1.7 mL), trifluoroacetic acid (0.51 mL, 6.6 mmol)and trifluoromethanesulfonic acid (0.09 mL, 1.0 mmol) were added, andthe mixture was stirred at room temperature for 4 hours. The reactionmixture was poured into a mixture of sodium bicarbonate (0.65 g, 7.7mmol) and water (3.4 mL), and the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was concentrated underreduced pressure, and the concentrated mixture was diluted by additionof tetrahydrofuran (3.4 mL). 2 N sulfuric acid (0.34 mL, 0.68 mmol) wasadded thereto, and the mixture was stirred at room temperature for 1hour. To the reaction mixture, a 2 N aqueous sodium hydroxide solution(0.34 mL, 0.68 mmol) was added, and the mixture was concentrated underreduced pressure. To the concentrated mixture, a saturated aqueoussolution of sodium chloride was added, and the mixture was washed withethyl acetate. The aqueous layer was rendered acidic by the addition of1 N hydrochloric acid, followed by extraction with a mixed solvent ofchloroform/isopropanol=3/1 twice. The organic layer was dried overanhydrous magnesium sulfate. After filtration, the solvent was distilledoff under reduced pressure. To the residue, ethyl acetate was added, andthe precipitated solid was collected by filtration, washed with ethylacetate, and then dried to obtain the title compound (113 mg, yield:85%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.27 (1H, br s), 8.34 (1H, br d,J=3.9 Hz), 8.24 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz), 7.51-7.47(2H, m), 7.26-7.22 (1H, m), 5.04 (1H, t, J=5.5 Hz), 4.38-4.32 (2H, m),3.86 (3H, s), 3.50-3.38 (3H, m).

MS spectrum (ES/APCI⁺): 398 (M+H).

(Example 29)5-Bromo-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

(29a)N-[(3S)-3-[(Benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-bromo-2-methoxybenzenesulfonamide

To a mixture of(3S)-7-amino-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(200 mg, 0.45 mmol) obtained in Example (27d) and pyridine (0.72 mL, 8.9mmol), 5-bromo-2-methoxybenzenesulfonyl chloride (140 mg, 0.49 mmol) wasadded, and the mixture was stirred at 80° C. for 2 hours in an oil bath.The reaction mixture was cooled and then concentrated under reducedpressure, and the residue was purified in an automatic chromatographyapparatus (n-hexane/ethyl acetate=100/0-0/100) to obtain the titlecompound (318 mg, yield: quantitative).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.37 (1H, d, J=2.7 Hz), 8.30 (1H, d,J=2.7 Hz), 7.87 (1H, d, J=2.0 Hz), 7.60 (1H, dd, J=8.6, 2.3 Hz),7.33-7.21 (5H, m), 6.95 (2H, d, J=8.6 Hz), 6.44 (2H, d, J=6.7 Hz), 5.04(1H, d, J=14.5 Hz), 4.73 (1H, dd, J=12.9, 5.1 Hz), 4.49-4.39 (3H, m),4.08-4.05 (4H, m), 3.99 (1H, dd, J=12.3, 6.6 Hz), 3.79 (3H, s), 3.77(3H, s), 3.55 (1H, t, J=8.6 Hz), 3.44 (1H, dd, J=9.4, 6.6 Hz).

(29b)5-Bromo-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

To a solution ofN-[(3S)-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-bromo-2-methoxybenzenesulfonamide(318 mg, 0.46 mmol) obtained in Example (29a) and anisole (0.15 mL, 1.4mmol) in chloroform (2.5 mL), trifluoroacetic acid (0.7 mL, 9.1 mmol)and trifluoromethanesulfonic acid (0.12 mL, 1.4 mmol) were added, andthe mixture was stirred at room temperature for 2 hours. The reactionmixture was diluted by addition of water (5 mL) and tetrahydrofuran (2.5mL) and stirred at room temperature for 1 hour. To the reaction mixture,sodium bicarbonate (0.92 g, 10.9 mmol) was carefully added, and themixture was stirred at room temperature for 10 minutes. To the mixture,a 2 N aqueous sodium hydroxide solution (0.5 mL, 1.0 mmol) was added,and the mixture was washed with ethyl acetate. To the aqueous layer, 2 Nhydrochloric acid (0.75 mL, 1.5 mmol) was added, followed by extractionwith a mixed solvent of chloroform/isopropanol=3/1. The organic layerwas dried over anhydrous sodium sulfate. After filtration, the solventwas distilled off under reduced pressure. To the residue, ethyl acetatewas added, and the precipitated solid was collected by filtration,washed with ethyl acetate, and then dried to obtain the title compound(147 mg, yield: 71%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.29 (1H, s), 8.36 (1H, d, J=3.9Hz), 8.23 (1H, d, J=2.7 Hz), 8.06 (1H, d, J=2.7 Hz), 7.80-7.76 (1H, m),7.75 (1H, d, J=2.7 Hz), 7.19 (1H, d, J=9.4 Hz), 5.05 (1H, t, J=5.3 Hz),4.37-4.35 (2H, m), 3.86 (3H, s), 3.50-3.38 (3H, m).

MS spectrum (ES/APCI⁺): 458 (M+H), 460 (M+2+H).

(Example 30)N-[(3S)-3-(Hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2,5-dimethoxybenzenesulfonamide

(30a)N-[(3S)-3-[(Benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2,5-dimethoxybenzenesulfonamide

To a mixture of(3S)-7-amino-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(180 mg, 0.40 mmol) obtained in Example (27d) and pyridine (0.65 mL, 8.0mmol), 2,5-dimethoxybenzenesulfonyl chloride (104 mg, 0.44 mmol) wasadded, and the mixture was stirred at 80° C. for 2 hours in an oil bath.The reaction mixture was cooled and then concentrated under reducedpressure, and the residue was purified in an automatic chromatographyapparatus (n-hexane/ethyl acetate=100/0-0/100) to obtain the titlecompound (266 mg, yield: quantitative).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.42 (1H, d, J=2.7 Hz), 8.30 (1H, d,J=2.7 Hz), 7.33-7.21 (8H, m), 7.03 (1H, dd, J=9.0, 3.1 Hz), 6.98 (1H, d,J=9.0 Hz), 6.45-6.41 (2H, m), 5.03 (1H, d, J=14.5 Hz), 4.71 (1H, dd,J=12.7, 5.3 Hz), 4.47-4.38 (3H, m), 4.06-3.95 (5H, m), 3.79 (3H, s),3.77 (3H, s), 3.73 (3H, s), 3.55 (1H, dd, J=9.6, 7.6 Hz), 3.42 (1H, dd,J=9.6, 6.5 Hz).

(30b)N-[(3S)-3-(Hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2,5-dimethoxybenzenesulfonamide

To a solution ofN-[(3S)-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2,5-dimethoxybenzenesulfonamide(266 mg, 0.41 mmol) obtained in Example (30a) and anisole (0.13 mL, 1.2mmol) in chloroform (2.5 mL), trifluoroacetic acid (0.63 mL, 8.2 mmol)and trifluoromethanesulfonic acid (0.11 mL, 1.2 mmol) were added, andthe mixture was stirred at room temperature for 2 hours. The reactionmixture was diluted by addition of water (5 mL) and tetrahydrofuran (2.5mL) and stirred at room temperature for 1 hour. To the reaction mixture,sodium bicarbonate (0.83 g, 9.8 mmol) was carefully added, and themixture was stirred at room temperature for 10 minutes. To the reactionmixture, a 2 N aqueous sodium hydroxide solution (0.5 mL, 1.0 mmol) wasadded, and the mixture was washed with ethyl acetate. To the aqueouslayer, 2 N hydrochloric acid (0.75 mL, 1.5 mmol) was added, followed byextraction with a mixed solvent of chloroform/isopropanol=3/1. Theorganic layer was dried over anhydrous sodium sulfate. After filtration,the solvent was distilled off under reduced pressure. To the residue,ethyl acetate was added, and the precipitated solid was collected byfiltration, washed with ethyl acetate, and then dried to obtain thetitle compound (74 mg, yield: 44%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.17 (1H, br s), 8.35 (1H, d,J=3.9 Hz), 8.25 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz), 7.21 (1H, d,J=2.7 Hz), 7.19-7.13 (2H, m), 4.36-4.32 (2H, m), 3.81 (3H, s), 3.72 (3H,s), 3.49-3.35 (3H, m).

MS spectrum (ES/APCI⁺): 410 (M+H).

(Example 31)5-Chloro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-(trifluoromethoxy)benzenesulfonamide

(31a)N-[(3S)-3-[(Benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-chloro-2-(trifluoromethoxy)benzenesulfonamide

To a mixture of(3S)-7-amino-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(220 mg, 0.49 mmol) obtained in Example (27d) and pyridine (0.79 mL, 9.8mmol), 5-chloro-2-(trifluoromethoxy)benzenesulfonyl chloride(approximately 83% content, 159 mg, 0.54 mmol) obtained in Example (13a)was added, and the mixture was stirred at 80° C. for 1 hour in an oilbath. The reaction mixture was cooled and then diluted by addition ofwater, followed by extraction with ethyl acetate. The organic layer waswashed with a saturated aqueous solution of sodium chloride and driedover anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure, and the residue was purified in anautomatic chromatography apparatus (n-hexane/ethyl acetate=100/0-65/35)to obtain the title compound (239 mg, yield: 69%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.45 (1H, d, J=2.7 Hz), 8.28 (1H, d,J=2.7 Hz), 7.88 (1H, d, J=2.7 Hz), 7.56 (1H, dd, J=8.8, 2.5 Hz),7.39-7.21 (7H, m), 6.99 (1H, br s), 6.46-6.42 (2H, m), 5.05 (1H, d,J=14.5 Hz), 4.75 (1H, dd, J=12.9, 5.1 Hz), 4.50-4.39 (3H, m), 4.10-4.00(2H, m), 3.79 (3H, s), 3.78 (3H, s), 3.55 (1H, dd, J=9.6, 7.6 Hz), 3.44(1H, dd, J=9.6, 6.5 Hz).

(31b)5-Chloro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-(trifluoromethoxy)benzenesulfonamide

To a solution ofN-[(3S)-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-chloro-2-(trifluoromethoxy)benzenesulfonamide(234 mg, 0.33 mmol) obtained in Example (31a) and anisole (0.11 mL, 1.0mmol) in chloroform (1.6 mL), trifluoroacetic acid (0.51 mL, 6.6 mmol)and trifluoromethanesulfonic acid (0.09 mL, 1.0 mmol) were added, andthe mixture was stirred at room temperature for 1 hour. The reactionmixture was diluted by addition of water (3.2 mL) and tetrahydrofuran(1.6 mL) and stirred at room temperature for 1 hour. To the reactionmixture, sodium bicarbonate (0.67 g, 7.9 mmol) was carefully added, andthe mixture was stirred at room temperature for 10 minutes. The reactionmixture was concentrated under reduced pressure. To the concentratedmixture, a 2 N aqueous sodium hydroxide solution (0.33 mL, 0.66 mmol)was added, and the mixture was washed with ethyl acetate. To the aqueouslayer, 1 N hydrochloric acid (0.66 mL, 0.66 mmol) was added, followed byextraction with a mixed solvent of methylene chloride/isopropanol=4/1.The organic layer was dried over anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure. To theresidue, ethyl acetate was added, and the precipitated solid wascollected by filtration, washed with ethyl acetate, and then dried toobtain the title compound (101 mg, yield: 65%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.77 (1H, br s), 8.41 (1H, br d,J=4.3 Hz), 8.21 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 7.91 (1H, d,J=2.7 Hz), 7.87 (1H, dd, J=8.8, 2.7 Hz), 7.64-7.60 (1H, m), 5.07 (1H, t,J=5.5 Hz), 4.43-4.34 (2H, m), 3.52-3.37 (3H, m).

MS spectrum (ESI⁺): 468 (M+H), 470 (M+2+H).

(Example 32)5-Fluoro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-(trifluoromethoxy)benzenesulfonamide

(32a) 5-Fluoro-2-(trifluoromethoxy)benzenesulfonyl chloride

The title compound (approximately 50% content, 2.49 g, yield: 81%) wasobtained as a mixture containing positional isomers by productionaccording to the method described in Example (13a) using 4-fluorophenyltrifluoromethyl ether (2.00 g, 11.1 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.87-7.82 (1H, m), 7.65-7.60 (0 5H,m), 7.57-7.47 (1H, m), 7.42 (0 5H, t, J=9.0 Hz).

(32b)N-[(3S)-3-[(Benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-(trifluoromethoxy)benzenesulfonamide

To a mixture of(3S)-7-amino-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(410 mg, 0.91 mmol) obtained in Example (27d) and pyridine (1.48 mL,18.2 mmol), 5-fluoro-2-(trifluoromethoxy)benzenesulfonyl chloride(approximately 50% content, 280 mg, 1.00 mmol) obtained in Example (32a)was added, and the mixture was stirred at 80° C. for 1 hour in an oilbath. The reaction mixture was cooled and then diluted by addition ofwater, followed by extraction with ethyl acetate. The organic layer waswashed with a saturated aqueous solution of sodium chloride and driedover anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure, and the residue was purified in anautomatic chromatography apparatus (n-hexane/ethyl acetate=100/0-65/35)to obtain the title compound (265 mg, yield: 42%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.44 (1H, d, J=2.7 Hz), 8.27 (1H, d,J=2.7 Hz), 7.61 (1H, dd, J=7.4, 3.1 Hz), 7.45-7.40 (1H, m), 7.34-7.22(7H, m), 7.01 (1H, br s), 6.46-6.42 (2H, m), 5.04 (1H, d, J=14.5 Hz),4.74 (1H, dd, J=12.9, 5.1 Hz), 4.49-4.39 (3H, m), 4.10-3.99 (2H, m),3.79 (3H, s), 3.78 (3H, s), 3.55 (1H, dd, J=9.6, 7.6 Hz), 3.43 (1H, dd,J=9.6, 6.3 Hz).

(32c)5-Fluoro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-(trifluoromethoxy)benzenesulfonamide

To a solution ofN-[(3S)-3-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-(trifluoromethoxy)benzenesulfonamide(258 mg, 0.37 mmol) obtained in Example (32b) and anisole (0.12 mL, 1.1mmol) in chloroform (1.8 mL), trifluoroacetic acid (0.57 mL, 7.5 mmol)and trifluoromethanesulfonic acid (0.10 mL, 1.1 mmol) were added, andthe mixture was stirred at room temperature for 1 hour. The reactionmixture was diluted by addition of water (3.6 mL) and tetrahydrofuran(1.8 mL) and stirred at room temperature for 1 hour. To the reactionmixture, sodium bicarbonate (0.75 g, 9.0 mmol) was carefully added, andthe mixture was stirred at room temperature for 10 minutes. The reactionmixture was concentrated under reduced pressure. To the concentratedmixture, a 2 N aqueous sodium hydroxide solution (0.37 mL, 0.74 mmol)was added, followed by extraction with ethyl acetate. To the aqueouslayer, 1 N hydrochloric acid (0.75 mL, 0.75 mmol) was added, followed byextraction with a mixed solvent of methylene chloride/isopropanol=4/1.The organic layer was dried over anhydrous sodium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure. To theresidue, ethyl acetate was added, and the precipitated solid wascollected by filtration, washed with ethyl acetate, and then dried toobtain the title compound (135 mg, yield: 80%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.77 (1H, br s), 8.40 (1H, br d,J=4.3 Hz), 8.21 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 7.76-7.72(1H, m), 7.69-7.63 (2H, m), 5.07 (1H, t, J=5.3 Hz), 4.44-4.34 (2H, m),3.54-3.37 (3H, m).

MS spectrum (ESI⁺): 452 (M+H).

(Example 33)5-Chloro-N-[(3S)-3-(2-hydroxyethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

(33a)(6S)—N-(2,4-Dimethoxybenzyl)-2,2,11,11-tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodecan-6-amine

To a solution of tert-butyl [(2S)-1,4-dihydroxybutan-2-yl]carbamate(2.00 g, 9.74 mmol) in methylene chloride (50 mL), imidazole (1.99 g,11.5 mmol) and tert-butyl(chloro)diphenylsilane (5.89 g, 21.4 mmol) wereadded, and the mixture was stirred at room temperature for 2 hours. Thereaction mixture was diluted by addition of water, followed byextraction with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (n-hexane/ethyl acetate=100/0-90/10) to obtaintert-butyl[(6S)-2,2,11,11-tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodecan-6-yl]carbamate.To tert-butyl[(6S)-2,2,11,11-tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodecan-6-yl]carbamatethus obtained, trifluoroacetic acid (50 mL, 653 mmol) was added, and themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, and the residue was neutralizedby the addition of saturated sodium bicarbonate, followed by extractionwith ethyl acetate. The organic layer was washed with a saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate. After filtration, the solvent was distilled off under reducedpressure to obtain a crude product of(6S)-2,2,11,11-tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodecan-6-amine.To a solution of the crude product of(6S)-2,2,11,11-tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodecan-6-aminethus obtained in methanol (9.35 mL), 2,4-dimethoxybenzaldehyde (2.11 g,12.7 mmol) and triethylamine (9.56 mL, 69.2 mmol) were added, and themixture was stirred at room temperature for 1 hour. Subsequently, to thereaction mixture, anhydrous sodium sulfate (0.901 g, 6.34 mmol) wasadded, and the mixture was stirred at room temperature for 18 hours.Subsequently, to the reaction mixture, sodium borohydride (0.24 g, 6.34mmol) was added under ice cooling, and the reaction mixture was stirredat the same temperature as above for 1 hour. The reaction mixture wasdiluted by addition of a saturated aqueous solution of sodiumbicarbonate, followed by extraction with ethyl acetate. The organiclayer was washed with a saturated aqueous solution of sodium chlorideand dried over anhydrous sodium sulfate. After filtration, the solventwas distilled off under reduced pressure, and the residue was purifiedin an automatic chromatography apparatus (n-hexane/ethylacetate=100/0-40/60) to obtain the title compound (8.08 g, yield for 3steps: quantitative).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.70-7.59 (8H, m), 7.45-7.30 (12H,m), 7.04 (1H, d, J=8.2 Hz), 6.51-6.35 (2H, m), 3.82 (3H, s), 3.81 (3H,s), 3.74-3.51 (6H, m), 2.90-2.75 (1H, m), 1.77-1.56 (2H, m).

(33b)(3S)-4-(2,4-Dimethoxybenzyl)-3-(2-hydroxyethyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

To a suspension of 2-chloro-5-nitropyridine-3-carboxylic acid (2.24 g,11.04 mmol) in methylene chloride (110 mL), oxalyl chloride (1.42 mL,16.6 mmol) and N,N-dimethylformamide (1.42 mL, 5.52 mmol) were added atroom temperature, and the mixture was stirred at the same temperature asabove for 2 hours. The reaction mixture was concentrated under reducedpressure to prepare a crude product of2-chloro-5-nitropyridine-3-carboxylic acid chloride. Subsequently, to asolution of(6S)—N-(2,4-dimethoxybenzyl)-2,2,11,11-tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodecan-6-amine(8.08 g, 11.04 mmol) obtained in Example (33a) andN,N-diisopropylethylamine (3.85 mL, 22.1 mmol) in tetrahydrofuran (110mL), a solution of the crude product of2-chloro-5-nitropyridine-3-carboxylic acid chloride in tetrahydrofuran(20 mL) was added under ice cooling, and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was diluted by addition ofwater, followed by extraction with ethyl acetate. The organic layer waswashed with a saturated aqueous solution of sodium chloride and driedover anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure, and the residue was purified in anautomatic chromatography apparatus (n-hexane/ethyl acetate=100/0-80/20)to obtain2-chloro-N-(2,4-dimethoxybenzyl)-5-nitro-N-[(6S)-2,2,11,11-tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodecan-6-yl]pyridine-3-carboxamide(7.193 g, yield: 71%). To a solution of2-chloro-N-(2,4-dimethoxybenzyl)-5-nitro-N-[(6S)-2,2,11,11-tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodecan-6-yl]pyridine-3-carboxamide(1.09 g, 1.19 mmol) thus obtained in tetrahydrofuran (15 mL), a solutionof tetrabutylammonium fluoride in tetrahydrofuran (1 mol/L, 3.57 mL,3.57 mmol) was added under ice cooling, and the mixture was stirred atroom temperature for 24 hours. The reaction mixture was diluted byaddition of a saturated aqueous solution of ammonium chloride, followedby extraction with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (n-hexane/ethyl acetate=100/0-0/100) to obtainthe title compound (233 mg, yield: 49%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.58 (1H, d, J=2.5 Hz), 9.19 (1H, d,J=2.5 Hz), 7.37 (1H, d, J=8.2 Hz), 6.52-6.47 (2H, m), 5.12 (1H, d,J=14.3 Hz), 4.76 (1H, dd, J=12.9, 5.5 Hz), 4.48 (1H, d, J=14.3 Hz),4.31-4.22 (2H, m), 3.84 (3H, s), 3.81 (3H, s), 3.79-3.67 (2H, m),1.89-1.79 (1H, m), 1.75-1.65 (1H, m).

(33c)(3S)-7-Amino-4-(2,4-dimethoxybenzyl)-3-(2-hydroxyethyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (60.0 mg, yield: quantitative) was obtained byproduction according to the method described in Example (3c) using(3S)-4-(2,4-dimethoxybenzyl)-3-(2-hydroxyethyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(64.0 mg, 0.16 mmol) obtained in Example (33b).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.09 (1H, d, J=2.7 Hz), 7.86 (1H, d,J=2.7 Hz), 7.33-7.31 (1H, m), 6.48-6.46 (2H, m), 5.10 (1H, d, J=14.5Hz), 4.54 (1H, dd, J=12.9, 5.5 Hz), 4.45 (1H, d, J=14.5 Hz), 4.08 (1H,d, J=12.9 Hz), 4.05-3.97 (1H, m), 3.82 (3H, s), 3.80 (3H, s), 3.76-3.49(5H, m), 1.90-1.70 (2H, m).

(33d)5-Chloro-N-[(3S)-4-(2,4-dimethoxybenzyl)-3-(2-hydroxyethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

The title compound (67 mg, yield: 72%) was obtained by productionaccording to Example (1d) using(3S)-7-amino-4-(2,4-dimethoxybenzyl)-3-(2-hydroxyethyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(60.0 mg, 0.16 mmol) obtained in Example (33c) and5-chloro-2-methoxybenzenesulfonyl chloride (42.6 mg, 0.18 mmol).

¹H NMR spectrum (CDCl3, 400 MHz) δ: 8.40 (1H, d, J=2.7 Hz), 8.30 (1H, d,J=2.7 Hz), 7.74 (1H, dd, J=3.7, 2.5 Hz), 7.49-7.43 (1H, m), 7.34-7.24(1H, m), 7.00 (1H, dd, J=9.0, 3.9 Hz), 6.48-6.43 (2H, m), 5.08 (1H, dd,J=14.4, 3.6 Hz), 4.59 (1H, dt, J=12.7, 4.7 Hz), 4.41 (1H, dd, J=14.4,3.6 Hz), 4.15-4.03 (8H, m), 3.80 (3H, s), 3.75-3.62 (2H, m), 1.85-1.58(2H, m).

(33e)5-Chloro-N-[(3S)-3-(2-hydroxyethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

The title compound (42 mg, yield: 85%) was obtained by productionaccording to the method described in Example (9) using5-chloro-N-[(3S)-4-(2,4-dimethoxybenzyl)-3-(2-hydroxyethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide(67 mg, 0.12 mmol) obtained in Example (33d).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.29 (1H, br s), 8.48 (1H, d,J=5.9 Hz), 8.14 (1H, d, J=2.7 Hz), 8.08 (1H, d, J=2.7 Hz), 7.68 (1H, d,J=2.4 Hz), 7.65 (1H, dd, J=5.9, 2.4 Hz), 7.25 (1H, d, J=8.8 Hz),4.32-4.29 (2H, m), 3.87 (3H, s), 3.63-3.40 (3H, m), 1.60-1.55 (2H, m).

MS spectrum (ES/APCI⁺): 428 (M+H), 430 (M+2+H).

(Example 34)2-[(3S)-7-{[(5-Chloro-2-methoxyphenyl)sulfonyl]amino}-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-3-yl]-N,N-dimethylacetamide

(34a)2-[(3S)-4-(2,4-Dimethoxybenzyl)-7-nitro-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-3-yl]-N,N-dimethylacetamide

To a mixture of(3S)-4-(2,4-dimethoxybenzyl)-3-(2-hydroxyethyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(120 mg, 0.30 mmol) obtained in Example (33b) in acetonitrile (3 mL) anda phosphate buffer solution (pH 6.86) (2 mL), 2-azaadamantane-N-oxyl(45.3 mg, 0.030 mmol) and sodium chlorate (32.3 mg, 0.036 mmol) wereadded, subsequently an aqueous sodium hypochlorite solution (availablechlorine concentration: >5%, 2.35 mL, 0.9 mmol) was added under icecooling, and the mixture was stirred for 3 hours under ice cooling. Thereaction mixture was diluted by addition of a saturated aqueous solutionof sodium thiosulfate and a saturated aqueous solution of ammoniumchloride, followed by extraction with ethyl acetate. The organic layerwas washed with a saturated aqueous solution of sodium chloride anddried over anhydrous sodium sulfate. After filtration, the solvent wasdistilled off under reduced pressure to obtain a crude product of[(3S)-4-(2,4-dimethoxybenzyl)-7-nitro-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-3-yl]aceticacid. To a solution of the crude product of[(3S)-4-(2,4-dimethoxybenzyl)-7-nitro-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-3-yl]aceticacid thus obtained in N,N-dimethylformamide (10 mL), dimethylaminehydrochloride (36.3 mg, 0.45 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 mg,0.59 mmol), 1-hydroxybenzotriazole monohydrate (91.0 mg, 0.59 mmol), andtriethylamine (0.206 mL, 1.49 mmol) were added, and the mixture wasstirred at room temperature for 17 hours. The reaction mixture wasdiluted by addition of water, followed by extraction with ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure, and the residue waspurified in an automatic chromatography apparatus (ethylacetate/methanol=100/0-85/15) to obtain the title compound (108 mg,yield for 2 steps: 82%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.62 (1H, d, J=2.7 Hz), 9.21 (1H,dd, J=4.9, 2.7 Hz), 7.44-7.36 (1H, m), 6.52-6.45 (2H, m), 5.00-4.90 (2H,m), 4.70-4.56 (2H, m), 4.28 (1H, d, J=12.5 Hz), 3.82 (3H, s), 3.80 (3H,s), 2.85 (3H, s), 2.82 (3H, s), 2.61 (1H, td, J=16.2, 9.4 Hz), 2.39 (1H,dq, J=16.2, 4.4 Hz).

(34b)2-[(3S)-7-Amino-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-3-yl]-N,N-dimethylacetamide

The title compound (90.0 mg, yield: 89%) was obtained by productionaccording to the method described in Example (3c) using2-[(3S)-4-(2,4-dimethoxybenzyl)-7-nitro-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-3-yl]-N,N-dimethylacetamide(108 mg, 0.24 mmol) obtained in Example (34a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.14 (1H, t, J=2.9 Hz), 7.90 (1H, t,J=3.5 Hz), 7.40-7.30 (1H, m), 6.50-6.43 (2H, m), 4.93 (1H, t, J=15.3Hz), 4.70 (1H, dq, J=12.6, 2.5 Hz), 4.55 (1H, dd, J=14.5, 3.9 Hz),4.52-4.45 (1H, m), 4.08 (1H, dd, J=12.6, 6.8 Hz), 3.91 (3H, s), 3.79(3H, s), 2.92 (3H, s), 2.85 (3H, s), 2.76-2.64 (1H, m), 2.37 (1H, td,J=10.6, 5.5 Hz).

(34c)2-[(3S)-7-{[(5-Chloro-2-methoxyphenyl)sulfonyl]amino}-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-3-yl]-N,N-dimethylacetamide

The title compound (40 mg, yield: 30%) was obtained by productionaccording to Example (1d) using2-[(3S)-7-amino-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-3-yl]-N,N-dimethylacetamide(90.0 mg, 0.22 mmol) obtained in Example (34b) and5-chloro-2-methoxybenzenesulfonyl chloride (57.6 mg, 0.24 mmol).

¹H NMR spectrum (CDCl3, 400 MHz) δ: 8.43 (1H, d, J=2.7 Hz), 8.30 (1H, d,J=2.7 Hz), 7.73 (1H, d, J=2.4 Hz), 7.46 (1H, dd, J=8.9, 2.7 Hz),7.32-7.24 (1H, m), 7.01 (1H, dd, J=8.9, 2.4 Hz), 6.49-6.42 (2H, m), 4.91(1H, d, J=14.1 Hz), 4.75 (1H, dd, J=12.7, 5.3 Hz), 4.56-4.46 (2H, m),4.06 (3H, s), 3.91-3.83 (1H, m), 3.78 (3H, s), 3.78 (3H, s), 2.91 (3H,s), 2.79 (3H, s), 2.58 (1H, dd, J=16.0, 9.4 Hz), 2.31 (1H, dd, J=16.0,4.7 Hz).

(34d)2-[(3S)-7-{[(5-Chloro-2-methoxyphenyl)sulfonyl]amino}-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-3-yl]-N,N-dimethylacetamide

The title compound (12 mg, yield: 40%) was obtained by productionaccording to the method described in Example (9) using2-[(3S)-7-{[(5-chloro-2-methoxyphenyl)sulfonyl]amino}-4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-3-yl]-N,N-dimethylacetamide(40.0 mg, 0.065 mmol) obtained in Example (34c).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.32 (1H, br s), 8.19 (1H, d,J=2.7 Hz), 8.09 (1H, d, J=2.7 Hz), 7.68-7.65 (2H, m), 7.25 (1H, d, J=8.6Hz), 4.40-4.28 (2H, m), 3.92-3.83 (4H, m), 3.80-3.74 (1H, m), 2.88 (3H,s), 2.82 (3H, s), 2.79-2.64 (2H, m).

MS spectrum (ES/APCI⁺): 469 (M+H), 471 (M+2+H).

(Example 35)5-Chloro-2-methoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide

(35a) {1-[(2,4-Dimethoxybenzyl)amino]cyclopropyl}methanol

The title compound (1.90 g, yield: 91%) was obtained by productionaccording to the method described in Example (8a) using(1-aminocyclopropyl)methanol (0.75 g, 0.24 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.14 (1H, d, J=8.2 Hz), 6.46-6.42(2H, m), 3.83 (3H, s), 3.79 (3H, s), 3.74 (2H, s), 3.51 (2H, s), 3.48(1H, s), 0.70-0.68 (2H, m), 0.52-0.49 (2H, m).

(35b)2-Chloro-N-(2,4-dimethoxybenzyl)-N-[1-(hydroxymethyl)cyclopropyl]-5-nitropyridine-3-carboxamide

To a suspension of 2-chloro-5-nitropyridine-3-carboxylic acid (1.587 g,7.83 mmol) in methylene chloride (80 mL), oxalyl chloride (0.84 mL, 9.8mmol) and N,N-dimethylformamide (0.30 mL, 3.92 mmol) were added at roomtemperature, and the mixture was stirred at the same temperature asabove for 2 hours. The reaction mixture was concentrated under reducedpressure to prepare a crude product of2-chloro-5-nitropyridine-3-carboxylic acid chloride. To a solution of{1-[(2,4-dimethoxybenzyl)amino]cyclopropyl}methanol (1.859 g, 7.83 mmol)obtained in Example (35a) and N,N-diisopropylethylamine (2.73 mL, 15.7mmol) in tetrahydrofuran (60 mL), a solution of the crude product of2-chloro-5-nitropyridine-3-carboxylic acid chloride in tetrahydrofuran(20 mL) was added under ice cooling, and the reaction mixture wasstirred at room temperature for 30 minutes. The reaction mixture wasdiluted by addition of water, followed by extraction with ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure, and the residue waspurified in an automatic chromatography apparatus (n-hexane/ethylacetate=100/0-40/60) to obtain the title compound (2.155 g, yield: 65%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.25 (0.14H, d, J=2.7 Hz), 9.19(0.86H, d, J=2.7 Hz), 8.47 (0.14H, d, J=2.7 Hz), 7.06 (1H, br d, J=8.2Hz), 6.43-6.36 (2H, m), 4.04-3.03 (11H, m), 1.28-1.23 (4H, m).

(35c)4′-(2,4-Dimethoxybenzyl)-7′-nitrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one

To a solution of2-chloro-N-(2,4-dimethoxybenzyl)-N-[1-(hydroxymethyl)cyclopropyl]-5-nitropyridine-3-carboxamide(400 mg, 0.95 mmol) obtained in Example (35b) in N,N-dimethylformamide(47 mL), potassium carbonate (393 mg, 2.84 mmol) was added, and themixture was stirred at room temperature for 22 hours and subsequentlystirred at 50° C. for 2 hours and at 70° C. for 2 hours. The reactionmixture was cooled, and insoluble matter was filtered off. The residuewas washed with ethyl acetate. The filtrate and the washes werecombined. The solvent was distilled off under reduced pressure, and theresidue was purified in an automatic chromatography apparatus(n-hexane/ethyl acetate=100/0-50/50) to obtain the title compound (238mg, yield: 65%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.23-9.19 (1H, m), 9.11-9.08 (1H,m), 7.22 (1H, d, J=7.8 Hz), 6.49-6.45 (2H, m), 4.27-4.08 (3H, m),3.92-3.74 (7H, m), 1.32-1.20 (2H, m), 0.97-0.87 (2H, m).

(35d)7′-Amino-4′-(2,4-dimethoxybenzyl)spiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one

A mixture of4′-(2,4-dimethoxybenzyl)-7′-nitrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one(238 mg, 0.62 mmol) obtained in Example (35c) and 10% palladium carbon(water content: 54.6%, 100 mg) in tetrahydrofuran (30 mL), and methanol(30 mL) was stirred at room temperature for 3 hours at normal pressureunder the hydrogen atmosphere. Hydrogen in the reaction container wasreplaced with nitrogen, and then, the reaction mixture was filteredthrough pad of Celite 545(R). The solvent in the filtrate was distilledoff under reduced pressure to obtain the title compound (227 mg, yield:quantitative).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.84 (1H, d, J=2.2 Hz), 7.48 (1H, d,J=2.2 Hz), 7.20 (1H, d, J=8.2 Hz), 6.48-6.43 (2H, m), 4.70 (2H, br s),3.82 (3H, s), 3.81 (3H, s), 3.69 (2H, s), 3.48 (2H, d, J=3.1 Hz), 0.93(2H, br s), 0.63 (2H, br s).

(35e)5-Chloro-2-methoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide

The title compound (80 mg, yield: 56%) was obtained by productionaccording to the method described in Examples (1d) and (9) using7′-amino-4′-(2,4-dimethoxybenzyl)spiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one (124 mg, 0.35 mmol) obtained in Example (35d) and5-chloro-2-methoxybenzenesulfonyl chloride (92.5 mg, 0.38 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.29 (1H, br s), 8.84 (1H, s),8.08 (1H, d, J=2.7 Hz), 7.94 (1H, d, J=2.7 Hz), 7.68-7.62 (2H, m), 7.25(1H, d, J=8.6 Hz), 4.26 (2H, s), 3.87 (3H, s), 0.74 (4H, br s).

MS spectrum (ES/APCI⁺): 410 (M+H), 412 (M+2+H).

(Example 36)5-Fluoro-2-methoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide

The title compound (81 mg, yield for 2 steps: 71%) was obtained byproduction according to the method described in Examples (1d) and (9)using7′-amino-4′-(2,4-dimethoxybenzyl)spiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one (103 mg, 0.29 mmol) obtained in Example (35d) and5-fluoro-2-methoxybenzenesulfonyl chloride (71.6 mg, 0.32 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.27 (1H, br s), 8.83 (1H, s),8.08 (1H, d, J=3.1 Hz), 7.95 (1H, d, J=3.1 Hz), 7.51-7.46 (2H, m),7.26-7.22 (1H, m), 4.25 (2H, s), 3.86 (3H, s), 0.74 (4H, br s).

MS spectrum (ES/APCI⁺): 394 (M+H).

(Example 37)5-Chloro-2-methoxy-N-(5-oxo-4-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

(37a) 7-Nitro-4-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (324 mg, yield for 2 steps: 39%) was obtained byproduction according to the method described in Examples (1a) and (35c)using 2-chloro-5-nitropyridine-3-carboxylic acid (591 mg, 2.92 mmol) and2-anilinoethanol (400 mg, 2.92 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.32 (1H, d, J=3.1 Hz), 9.28 (1H, d,J=3.1 Hz), 7.50-7.46 (2H, m), 7.39-7.35 (1H, m), 7.33-7.30 (2H, m),4.87-4.85 (2H, m), 4.15-4.13 (2H, m).

(37b) 7-Amino-4-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (243 mg, yield: 84%) was obtained by productionaccording to the method described in Example (3b) using7-nitro-4-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (324mg, 1.14 mmol) obtained in Example (37a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.93 (1H, d, J=3.1 Hz), 7.60 (1H, d,J=3.1 Hz), 7.46 (2H, t, J=7.6 Hz), 7.37-7.31 (3H, m), 4.58 (2H, t, J=5.1Hz), 3.96 (2H, t, J=5.1 Hz), 3.69 (2H, br s).

(37c)5-Chloro-2-methoxy-N-(5-oxo-4-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

The title compound (77 mg, yield: 71%) was obtained by productionaccording to Example (1d) using7-amino-4-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (60 mg,0.24 mmol) obtained in Example (37b) and5-chloro-2-methoxybenzenesulfonyl chloride (62 mg, 0.26 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.39 (1H, br s), 8.16 (1H, d,J=2.4 Hz), 7.98 (1H, d, J=2.4 Hz), 7.69-7.67 (2H, m), 7.44 (2H, t, J=7.3Hz), 7.36 (2H, d, J=7.3 Hz), 7.32-7.25 (2H, m), 4.56 (2H, t, J=4.6 Hz),3.95 (2H, t, J=4.6 Hz), 3.88 (3H, s).

MS spectrum (ES/APCI⁺): 460 (M+H), 462 (M+2+H).

(Example 38)5-Chloro-2-methoxy-N-[5-oxo-4-(pyridin-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

(38a) 7-Nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (1.24 g, yield: quantitative) was obtained byproduction according to Example (18c) using4-(2,4-dimethoxybenzyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(2.00 g, 5.57 mmol) obtained in Example (8c).

¹H NMR spectrum (CD₃OD, 400 MHz) δ: 9.30 (1H, d, J=2.7 Hz), 9.19 (1H, d,J=2.7 Hz), 4.70-4.69 (2H, m), 3.67-3.65 (2H, m).

(38b)7-Nitro-4-(pyridin-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

A mixture of 7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(100 mg, 0.48 mmol) obtained in Example (38a), 2-bromopyridine (90.6 mg,0.57 mmol), tris(dibenzylideneacetone)dipalladium(0) (87.6 mg, 0.010mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.1 mg, 0.019mmol), and cesium carbonate (0.312 g, 0.96 mmol) in dioxane (10 mL) washeated to reflux for 18 hours in an oil bath. The reaction mixture wascooled. The solvent was distilled off under reduced pressure, and theresidue was purified in an automatic chromatography apparatus(n-hexane/ethyl acetate/methanol=100/0/0-0/100/0-0/85/15) to obtain thetitle compound (41 mg, yield: 30%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.30 (1H, d, J=2.7 Hz), 9.25 (1H, d,J=2.7 Hz), 8.46-8.44 (1H, m), 8.06 (1H, d, J=8.2 Hz), 7.83-7.79 (1H, m),7.22-7.19 (1H, m), 4.90 (2H, t, J=4.3 Hz), 4.57 (2H, t, J=4.3 Hz.

(38c)5-Chloro-2-methoxy-N-[5-oxo-4-(pyridin-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

The title compound (58 mg, yield for 2 steps: 88%) was obtained byproduction according to Examples (3b) and (1d) using7-nitro-4-(pyridin-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(41.0 mg, 0.14 mmol) obtained in Example (38b) and5-chloro-2-methoxybenzenesulfonyl chloride (35.2 mg, 0.15 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.45 (1H, br s), 8.47 (1H, d,J=3.9 Hz), 8.18 (1H, br s), 7.95-7.86 (3H, m), 7.70-7.67 (2H, m),7.29-7.25 (2H, m), 4.53 (2H, br s), 4.30 (2H, br s), 3.88 (3H, s).

MS spectrum (ES/APCI⁺): 461 (M+H), 463 (M+2+H).

(Example 39)5-Chloro-2-methoxy-N-[5-oxo-4-(pyridin-3-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

(39a)7-Nitro-4-(pyridin-3-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (104 mg, yield: 76%) was obtained by productionaccording to the method described in Example (38b) using7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (100 mg, 0.48mmol) obtained in Example (38a) and 3-iodopyridine (118 mg, 0.57 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.34-9.30 (2H, m), 8.62-8.61 (2H,m), 7.74-7.71 (1H, m), 7.44 (1H, dd, J=8.0, 4.9 Hz), 4.89 (2H, t, J=4.1Hz), 4.18 (2H, t, J=4.1 Hz).

(39b)5-Chloro-2-methoxy-N-[5-oxo-4-(pyridin-3-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

The title compound (13 mg, yield for 2 steps: 8%) was obtained byproduction according to the method described in Examples (3b) and (1d)using7-nitro-4-(pyridin-3-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(104 mg, 0.36 mmol) obtained in Example (39a) and5-chloro-2-methoxybenzenesulfonyl chloride (21.7 mg, 0.09 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.40 (1H, br s), 8.62 (1H, d,J=2.4 Hz), 8.50-8.49 (1H, m), 8.18 (1H, d, J=2.9 Hz), 8.01 (1H, d, J=2.9Hz), 7.84 (1H, br d, J=8.3 Hz), 7.69-7.67 (2H, m), 7.49 (1H, dd, J=8.1,4.6 Hz), 7.27-7.25 (1H, m), 4.59 (2H, t, J=4.1 Hz), 4.01 (2H, t, J=4.1Hz), 3.88 (3H, s).

MS spectrum (ES/APCI⁺): 461 (M+H), 463 (M+2+H).

(Example 40)5-Chloro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)-2-(trifluoromethoxy)benzenesulfonamide

(40a) 5-Chloro-2-(trifluoromethoxy)benzenesulfonyl chloride

To a suspension of 5-chloro-2-(trifluoromethoxy)aniline (5.00 g, 23.6mmol) and dibenzyl disulfide (4.66 g, 18.9 mmol) in acetonitrile (75mL), Isoamyl nitrite (3.46 mL, 26.0 mmol) was slowly added at 60° C. inan oil bath, and the mixture was stirred at the same temperature asabove for 2 hours. The reaction mixture was cooled and then concentratedunder reduced pressure, and the residue was purified in an automaticchromatography apparatus (n-hexane/ethyl acetate=100/0-95/5) to prepare2-(benzylsulfanyl)-4-chlorophenyl trifluoromethyl ether (3.86 g, yield:51%). To a mixture of the obtained 2-(benzylsulfanyl)-4-chlorophenyltrifluoromethyl ether (4.84 g, 15.2 mmol), acetic acid (4.5 mL) andwater (3 mL) in acetonitrile (120 mL),1,3-dichloro-5,5-dimethylhydantoin (5.98 g, 30.4 mmol) was added underice cooling, and the mixture was stirred at the same temperature asabove for 3 hours. The mixture was diluted by addition of a saturatedaqueous solution of sodium bicarbonate, extracted with ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. After filtration, thesolvent was distilled off under reduced pressure, and the residue waspurified in an automatic chromatography apparatus (hexane/ethylacetate=100/0-85/15) to obtain the title compound (3.64 g, yield: 81%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.09 (1H, d, J=2.3 Hz), 7.75 (1H,dd, J=9.0, 2.7 Hz), 7.50-7.47 (1H, m).

(40b)5-Chloro-N-[4′-(2,4-dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-2-(trifluoromethoxy)benzenesulfonamide

To a mixture of7′-amino-4′-(2,4-dimethoxybenzyl)spiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one (95.0 mg, 0.267 mmol) obtained in Example (35d) and pyridine(0.432 mL, 5.35 mmol), 5-chloro-2-(trifluoromethoxy)benzenesulfonylchloride (86.8 mg, 0.294 mmol) in Example (40a) was added at roomtemperature, and the mixture was stirred at 80° C. for 2 hours in an oilbath. The reaction mixture was cooled and then concentrated underreduced pressure, and the residue was purified in an automaticchromatography apparatus (ethyl acetate/methanol=100/0-90/10) to obtainthe title compound (142 mg, yield: 87%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.23 (1H, d, J=2.7 Hz), 7.91 (1H, d,J=2.7 Hz), 7.87 (1H, d, J=2.7 Hz), 7.57 (1H, dd, J=8.8, 2.5 Hz),7.39-7.35 (1H, m), 7.17 (1H, d, J=8.2 Hz), 6.46-6.44 (2H, m), 4.68 (1H,br s), 3.96 (1H, br s), 3.81 (3H, s), 3.80 (3H, s), 0.93 (2H, br s),0.69 (2H, br s).

(40c)5-Chloro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)-2-(trifluoromethoxy)benzenesulfonamide

To a solution of5-chloro-N-[4′-(2,4-dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-2-(trifluoromethoxy)benzenesulfonamide(142 mg, 0.231 mmol) obtained in Example (40b) in chloroform (8 mL),anisole (0.0504 mL, 0.463 mmol), trifluoroacetic acid (4 mL, 52 mmol)and trifluoromethanesulfonic acid (0.0609 mL, 0.694 mmol) were added atroom temperature, and the mixture was stirred at room temperature for 2hours. The reaction mixture was diluted by addition of a saturatedaqueous solution of sodium bicarbonate under ice cooling, followed byextraction with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (ethyl acetate/methanol=100/0-90/10) to obtainthe title compound (84 mg, yield: 78%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.73 (1H, br s), 8.87 (1H, br s),8.11 (1H, d, J=2.4 Hz), 7.93-7.86 (3H, m), 7.61 (1H, d, J=8.8 Hz), 4.30(2H, br s), 0.80 (2H, br s), 0.77 (2H, br s).

MS spectrum (ES/APCI⁺): 464 (M+H), 466 (M+2+H).

(Example 41)5-Fluoro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)-2-(trifluoromethoxy)benzenesulfonamide

(41a) 5-Fluoro-2-(trifluoromethoxy)benzenesulfonyl chloride

The title compound (0.82 g, yield for 2 steps: 29%) was obtained byproduction according to the method described in Example (40a) using5-fluoro-2-(trifluoromethoxy)aniline (2.00 g, 10.3 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.84 (1H, dd, J=6.8, 2.9 Hz),7.56-7.47 (2H, m).

(41b)N-[4′-(2,4-Dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-5-fluoro-2-(trifluoromethoxy)benzenesulfonamide

To a mixture of7′-amino-4′-(2,4-dimethoxybenzyl)spiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one(100 mg, 0.281 mmol) obtained in Example (35d) and pyridine (0.453 mL,5.63 mmol), 5-fluoro-2-(trifluoromethoxy)benzenesulfonyl chloride (94.1mg, 0.338 mmol) in Example (41a) was added at room temperature, and themixture was stirred at 80° C. for 5 hours in an oil bath. The reactionmixture was cooled and then concentrated under reduced pressure, and theresidue was purified in an automatic chromatography apparatus(n-hexane/ethyl acetate=100/0-0/100) to obtain the title compound (156mg, yield: 93%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.27 (1H, d, J=2.7 Hz), 7.94 (1H, d,J=2.7 Hz), 7.63 (1H, dd, J=7.4, 3.1 Hz), 7.32-7.28 (2H, m), 7.16 (1H, d,J=8.2 Hz), 6.46-6.43 (2H, m), 4.69 (1H, br s), 3.95 (2H, br s), 3.81(3H, s), 3.80 (3H, s), 0.92 (2H, br s), 0.69 (2H, br s).

(41c)5-Fluoro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)-2-(trifluoromethoxy)benzenesulfonamide

To a suspension ofN-[4′-(2,4-dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-5-fluoro-2-(trifluoromethoxy)benzenesulfonamide(156 mg, 0.261 mmol) obtained in Example (41b) in chloroform (5 mL),anisole (84.7 mg, 0.783 mmol), trifluoroacetic acid (0.40 mL, 5.2 mmol)and trifluoromethanesulfonic acid (0.0687 mL, 0.783 mmol) were added atroom temperature, and the mixture was stirred at room temperature for 2hours. To the mixture, an additional trifluoroacetic acid (2 mL) wasadded, and the mixture was stirred at room temperature for further 2hours. The reaction mixture was diluted by addition of a saturatedaqueous solution of sodium bicarbonate under ice cooling, followed byextraction with chloroform. The organic layer was washed with asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (ethyl acetate/methanol=100/0-95/5) to obtainthe title compound (97 mg, yield: 83%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.75 (1H, br s), 8.88 (1H, br s),8.11 (1H, d, J=2.7 Hz), 7.92 (1H, d, J=2.7 Hz), 7.75-7.66 (3H, m), 4.30(2H, br s), 0.82-0.75 (4H, m).

MS spectrum (ES/APCI⁺): 448 (M+H).

(Example 42)2-Ethoxy-5-fluoro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide

(42a) 5-Fluoro-2-ethoxybenzenesulfonyl chloride

The title compound (3.16 g, yield: 36%) was obtained by productionaccording to the method described in Example (13a) using1-ethoxy-4-fluorobenzene (5.11 g, 36.5 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.70 (1H, dd, J=7.4, 3.1 Hz),7.41-7.36 (1H, m), 7.07 (1H, dd, J=9.4, 3.9 Hz), 4.26 (2H, q, J=6.8 Hz),1.55 (3H, t, J=6.8 Hz).

(42b)N-[4′-(2,4-Dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-2-ethoxy-5-fluorobenzenesulfonamide

To a mixture of7′-amino-4′-(2,4-dimethoxybenzyl)spiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one(100 mg, 0.281 mmol) obtained in Example (35d) and pyridine (0.453 mL,5.63 mmol), 5-Fluoro-2-ethoxybenzenesulfonyl chloride (73.9 mg, 0.310mmol) obtained in Example (42a) was added at room temperature, and themixture was stirred at 80° C. for 2 hours in an oil bath. The reactionmixture was cooled and then concentrated under reduced pressure, and theresidue was purified in an automatic chromatography apparatus(n-hexane/ethyl acetate=100/0-0/100) to obtain the title compound (146mg, yield: 93%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.20 (1H, d, J=2.7 Hz), 7.85 (1H, d,J=2.7 Hz), 7.47 (1H, dd, J=7.4, 3.1 Hz), 7.23-7.14 (2H, m), 7.02-6.95(2H, m), 6.46-6.43 (2H, m), 4.66 (1H, br s), 4.29 (2H, q, J=7.0 Hz),3.92 (1H, br s), 3.80 (3H, s), 3.79 (3H, s), 1.58 (3H, t, J=7.0 Hz),0.87 (2H, br s), 0.63 (2H, br s).

(42c)2-Ethoxy-5-fluoro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide

To a suspension ofN-[4′-(2,4-dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-2-ethoxy-5-fluorobenzenesulfonamide(146 mg, 0.262 mmol) obtained in Example (42b) in chloroform (4 mL),anisole (0.0571 mL, 0.524 mmol), trifluoroacetic acid (2 mL, 26.1 mmol)and trifluoromethanesulfonic acid (0.0689 mL, 0.786 mmol) were added atroom temperature, and the mixture was stirred at room temperature for 3hours. The reaction mixture was diluted by addition of a saturatedaqueous solution of sodium bicarbonate under ice cooling, followed byextraction with chloroform. The organic layer was washed with asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (ethyl acetate/methanol=100/0-90/10) to obtaina crude solid. To a suspension of the crude solid in ethanol (3 mL), a 1N aqueous sodium hydroxide solution (0.40 mL) was added and the mixturewas stirred at room temperature until dissolved. The mixture wasconcentrated under reduced pressure, diluted by addition of water, andthen filtered. A 1 N hydrochloric acid (0.40 mL) was added to thefiltrate, the precipitated solid was collected by filtration, washedwith water and ethanol, and then dried to obtain the title compound (95mg, yield: 89%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.15 (1H, s), 8.83 (1H, s), 8.09(1H, d, J=2.7 Hz), 7.95 (1H, d, J=2.7 Hz), 7.52-7.44 (2H, m), 7.24 (1H,dd, J=9.0, 4.3 Hz), 4.26 (br 2H, s), 4.16 (2H, q, J=7.0 Hz), 1.26 (3H,t, J=7.0 Hz), 0.77-0.71 (4H, m).

MS spectrum (ES/APCI⁺): 408 (M+H).

(Example 43)2,5-Dimethoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide

(43a)N-[4′-(2,4-Dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-2,5-dimethoxybenzenesulfonamide

To a mixture of7′-amino-4′-(2,4-dimethoxybenzyl)spiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one (90.0 mg, 0.253 mmol) obtained in Example (35d) and pyridine(0.408 mL, 5.06 mmol), 2,5-dimethoxybenzenesulfonyl chloride (65.9 mg,0.279 mmol) was added at room temperature, and the mixture was stirredat 80° C. for 3 hours in an oil bath. The reaction mixture was cooledand then concentrated under reduced pressure, and the residue waspurified in an automatic chromatography apparatus (n-hexane/ethylacetate=100/0-0/100) to obtain the title compound (143 mg, yield:quantitative).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.22 (1H, d, J=2.7 Hz), 7.88 (1H, brd, J=2.7 Hz), 7.37-7.28 (2H, m), 7.15 (1H, br d, J=8.6 Hz), 7.04 (1H,dd, J=9.0, 3.1 Hz), 6.97 (1H, d, J=9.0 Hz), 6.45-6.43 (2H, m), 4.66 (2H,br s), 3.99 (3H, s), 3.91 (2H, br s), 3.80 (3H, s), 3.79 (3H, s), 3.73(3H, s), 0.86 (2H, br s), 0.61 (2H, br s).

(43b)2,5-Dimethoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide

To a suspension ofN-[4′-(2,4-dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-2,5-dimethoxybenzenesulfonamide(0.143 mg, 0.257 mmol) obtained in Example (43a) in chloroform (4 mL),anisole (0.0561 mL, 0.515 mmol), trifluoroacetic acid (2 mL, 26 mmol)and trifluoromethanesulfonic acid (0.0678 mL, 0.772 mmol) were addedunder ice cooling, the mixture was stirred at the same temperature asabove for 3 hours and subsequently stirred at room temperature for 2hours. The reaction mixture was diluted by addition of a saturatedaqueous solution of sodium bicarbonate under ice cooling, followed byextraction with chloroform. The organic layer was washed with asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. After filtration, the solvent was distilled off underreduced pressure, and the residue was purified in an automaticchromatography apparatus (ethyl acetate/methanol=100/0-90/10) to obtainthe crude solid. To a suspension of the crude solid in ethanol (3 mL), a1 N aqueous sodium hydroxide solution (1 mL) was added and the mixturewas stirred at room temperature until dissolved. The mixture wasconcentrated under reduce pressure, diluted by addition of ethyl acetateand water. Most of the organic solvent was distillated off under reducepressure, and then filtered. A 1 N hydrochloric acid (1 mL) was addedthe filtrate, the precipitated solid was collected by filtration, washedwith water and ethanol, and then dried to obtain the title compound (55mg, yield: 53%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.17 (1H, br s), 8.83 (1H, br s),8.07 (1H, d, J=2.7 Hz), 7.95 (1H, d, J=2.7 Hz), 7.20-7.15 (3H, m), 4.24(2H, br s), 3.81 (3H, s), 3.71 (3H, s), 0.74 (4H, br s).

MS spectrum (ES/APCI⁺): 406 (M+H).

(Example 44)5-Chloro-2-methoxy-N-[5-oxo-3-(pyridin-3-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

(44a) 2-[(2,4-Dimethoxybenzyl)amino]-2-(pyridin-3-yl)ethanol

The title compound (approximately 77% content, 0.9217 g, yield: 69%) asa mixture containing 2.5-dimethoxybenzylalcohol was obtained byproduction according to the method of Example (8a) using2,4-dimethoxybenzaldehyde (627.6 mg, 3.78 mmol) and2-amino-2-(pyridin-3-yl)ethanol (495.3 mg, 3.59 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.54-8.51 (1.32H, m), 7.70-7.68(0.66H, m), 7.29-7.26 (0.66H, m), 7.17 (0.34H, d, J=8.2 Hz), 7.03-7.01(0.66H, d, J=7.8 Hz), 6.48-6.40 (2H, m), 4.61 (0.68H, s), 3.85-3.79(6.66H, m), 3.76-3.70 (1.32H, m), 3.56-3.52 (1.32H, m).

(44b)4-(2,4-Dimethoxybenzyl)-7-nitro-3-(pyridin-3-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (283.2 mg, yield for 2 steps: 27%) was obtained byproduction according to the method described in Examples (1a) and (35c)using 2-chloro-5-nitropyridine-3-carboxylic acid (501.1 mg, 2.47 mmol)and 2-[(2,4-dimethoxybenzyl)amino]-2-(pyridin-3-yl)ethanol(approximately 77% content, 0.912 g, 2.44 mmol) obtained in Example(44a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.66 (1H, d, J=2.7 Hz), 9.10 (1H, d,J=2.7 Hz), 8.51 (1H, dd, J=4.7, 1.6 Hz), 8.42 (1H, br d, J=2.3 Hz), 7.42(1H, d, J=8.2 Hz), 7.35-7.32 (1H, m), 7.21-7.17 (1H, m), 6.49 (1H, dd,J=8.2, 2.3 Hz), 6.40 (1H, d, J=2.3 Hz), 5.19 (1H, d, J=5.3 Hz), 5.10(1H, d, J=14.5 Hz), 5.02 (1H, dd, J=13.1, 5.3 Hz), 4.56 (1H, d, J=13.3Hz), 4.50 (1H, d, J=14.5 Hz), 3.80 (3H, s), 3.72 (3H, s).

(44c)7-Amino-4-(2,4-dimethoxybenzyl)-3-(pyridin-3-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (270.0 mg, yield: quantitative) was obtained byproduction according to the method of Example (8d) using4-(2,4-dimethoxybenzyl)-7-nitro-3-(pyridin-3-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(287.5 mg, 0.659 mmol) obtained in example (44b).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.48 (1H, dd, J=4.9, 1.6 Hz), 8.40(1H, d, J=2.3 Hz), 8.20 (1H, d, J=2.7 Hz), 7.81 (1H, d, J=2.7 Hz),7.39-7.35 (2H, m), 7.17 (1H, dd, J=8.0, 4.9 Hz), 6.47 (1H, dd, J=8.2,2.3 Hz), 6.39 (1H, d, J=2.3 Hz), 5.10 (1H, d, J=14.5 Hz), 4.97 (1H, d,J=5.3 Hz), 4.75 (1H, dd, J=13.1, 5.3 Hz), 4.38-4.34 (2H, m), 3.80 (3H,s), 3.72 (3H, s), 3.60 (2H, br s).

(44d)5-Chloro-2-methoxy-N-[5-oxo-3-(pyridin-3-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

The title compound (191.0 mg, yield for 2 steps: 64%) was obtained byproduction according to the method described in Examples (1d) and (9)using7-amino-4-(2,4-dimethoxybenzyl)-3-(pyridine-3-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(267.5 mg, 0.66 mmol) obtained in Example (44c) and5-chloro-2-methoxybenzenesulfonyl chloride (166.7 mg, 0.69 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.33 (1H, br s), 8.93 (1H, br d,J=5.5 Hz), 8.48-8.46 (2H, m), 8.35 (1H, d, J=2.7 Hz), 8.04 (1H, d, J=2.7Hz), 7.70-7.69 (2H, m), 7.60-7.57 (1H, m), 7.33 (1H, dd, J=7.8, 4.7 Hz),7.26 (1H, d, J=9.0 Hz), 4.93 (1H, t, J=5.5 Hz), 4.78 (1H, dd, J=12.9,5.5 Hz), 4.51 (1H, br d, J=12.9 Hz).

MS spectrum (ES/APCI⁺): 461 (M+H), 463 (M+2+H).

(Example 45)7-{[(5-Chloro-2-methoxyphenyl)sulfonyl]amino}-N,N-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-3-carboxamide

(45a) O-Benzyl-N-[(benzyloxy) carbonyl]serine

To a suspension of O-benzylserine (5.00 g, 25.6 mmol) in 1,4-dioxane (50mL), a 2 N aqueous sodium hydroxide solution (26.8 mL, 53.8 mmol) wasadded, and the mixture was stirred at room temperature for 10 minutes.Subsequently, to the mixture, benzyl chloroformate (3.82 mL, 26.9 mmol)was added, and the mixture was stirred at room temperature for 3 hours.The reaction mixture was concentrated under reduce pressure, and dilutedby addition of a 5 N hydrochloric acid (10.8 mL, 54.2 mmol), followed byextraction with ethyl acetate. The organic layer was washed with waterand a saturated aqueous solution of sodium chloride, and dried overanhydrous magnesium sulfate. After filtration, the solvent was distilledoff under reduced pressure. To the residue, n-hexane (20 mL) and ethylacetate (1 mL) were added, and the precipitated solid was collected byfiltration, washed with n-hexane, and then dried to obtain the titlecompound (7.24 g, yield: 86%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.37-7.27 (10H, m), 5.64 (1H, br d,J=8.2 Hz), 5.15 (1H, br d, J=12.1 Hz), 5.11 (1H, br d, J=12.1 Hz),4.57-4.53 (3H, m), 3.96 (1H, br dd, J=9.4, 3.1 Hz), 3.72 (1H, br dd,J=9.4, 3.3 Hz).

(45b) Benzyl [3-(benzyloxy)-1-(dimethylamino)-1-oxopropan-2-yl]carbamate

To a solution of O-benzyl-N-[(benzyloxy)carbonyl]serine (1.50 g, 4.55mmol) obtained in example (45a),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.06 g,5.53 mmol) and 1-hydroxybenzotriazole (0.68 g, 5.0 mmol) in methylenechloride (22 mL), dimethylamine in tetrahydrofuran (2.0 mol/L, 5.5 mL,11 mmol) was added under ice cooling, and the mixture was stirred at thesame temperature as above for 10 minutes and subsequently at roomtemperature for 1 hour. The mixture was diluted by addition of a 1 Nhydrochloric acid (50 mL), followed by extraction with ethyl acetate.The organic layer was washed with water, a saturated aqueous solution ofsodium bicarbonate and a saturated aqueous solution of sodium chloride,and dried over anhydrous magnesium sulfate. After filtration, thesolvent was distilled off under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/n-hexane=2/1-1/0) to obtain the title compound (1.47 g, yield:91%)

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.35-7.26 (10H, m), 5.75 (1H, d,J=8.2 Hz), 5.10 (2H, br s), 4.95-4.90 (1H, m), 4.54 (1H, d, J=12.1 Hz),4.49 (1H, d, J=12.1 Hz), 3.66 (1H, dd, J=9.4, 5.5 Hz), 3.59 (1H, dd,J=9.4, 7.0 Hz), 3.05 (3H, s), 2.97 (3H, s).

(45c) N,N-Dimethylserinamide

A mixture of benzyl[3-(benzyloxy)-1-(dimethylamino)-1-oxopropan-2-yl]carbamate (1.46 g,4.10 mmol) obtained in Example (45b) and 10% palladium carbon (watercontent: 54.6%, 0.28 g) in ethanol (41 mL) was stirred at roomtemperature for 1 hour at normal pressure under the hydrogen atmosphere.Subsequently the mixture was stirred at 50° C. for 24 hours in an oilbath at normal pressure under the hydrogen atmosphere. Hydrogen in thereaction container was replaced with nitrogen, and then, the reactionmixture was filtered through pad of Celite 545(R). The solvent in thefiltrate was distilled off under reduced pressure to obtain the titlecompound (approximately 70% content, 0.60 g, yield: 78%) as a mixturecontaining O-benzyl-N,N-dimethylserinamide

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.36-7.29 (1H, m), 4.53 (0.4H, brs), 3.98 (0.2H, dd, J=7.0, 5.9 Hz), 3.77 (0.8H, dd, J=7.0, 4.7 Hz), 3.66(0.8H, dd, J=10.9, 4.7 Hz), 3.57 (0.2H, dd, J=9.2, 5.9 Hz), 3.50-3.44(1H, m), 3.10 (2.4H, s), 3.04 (0.6H, s), 2.98 (2.4H, s), 2.97 (0.6H, s).

(45d) N²-(2,4-Dimethoxybenzyl)-N,N-dimethylserinamide

The title compound (0.76 g, yield: 85%) was obtained by productionaccording to the method of Example (8a) using 2,4-dimethoxybenzaldehyde(0.68 g, 4.1 mmol) and N,N-dimethylserinamide (approximately 70%content, 0.60 g, 3.2 mmol) obtained in Example (45c).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.14 (1H, d, J=7.8 Hz), 6.44-6.41(2H, m), 3.82 (3H, s), 3.80 (3H, s), 3.73-3.63 (3H, m) 3.59 (1H, dd,J=7.8, 4.7 Hz), 3.37 (1H, dd, J=10.2, 7.8 Hz), 2.99 (3H, s), 2.89 (3H,s).

(45e)4-(2,4-Dimethoxybenzyl)-N,N-dimethyl-7-nitro-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-3-carboxamide

The title compound (0.55 g, yield for 2 steps: 46%) was obtained byproduction according to the method described in Examples (1a) and (35c)using 2-chloro-5-nitropyridine-3-carboxylic acid (0.55 g, 2.7 mmol) andN²-(2,4-dimethoxybenzyl)-N,N-dimethylserinamide (0.76 g, 2.7 mmol)obtained in example (45d).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.73 (1H, d, J=2.7 Hz), 9.12 (1H, d,J=2.7 Hz), 7.37 (1H, d, J=8.2 Hz), 6.51-6.47 (2H, m), 5.04 (1H, d,J=14.5 Hz), 4.95-4.89 (2H, m), 4.43 (1H, d, J=14.5 Hz), 4.34 (1H, d,J=12.1 Hz), 3.83 (3H, s), 3.81 (3H, s), 3.04 (3H, s), 2.88 (3H, s).

(45f)7-Amino-4-(2,4-dimethoxybenzyl)-N,N-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-3-carboxamide

The title compound (342.7 mg, yield: 67%) was obtained by productionaccording to the method of Example (8d) using4-(2,4-dimethoxybenzyl)-N,N-dimethyl-7-nitro-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-3-carboxamide(552.0 mg, 1.24 mmol) obtained in Example (45e).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.19 (1H, d, J=2.7 Hz), 7.79 (1H, d,J=2.7 Hz), 7.35 (1H, d, J=8.2 Hz), 6.49-6.45 (2H, m), 5.09 (1H, d,J=14.5 Hz), 4.79-4.73 (2H, m), 4.31 (1H, d, J=14.5 Hz), 4.18-4.13 (1H,m), 3.81 (3H, s), 3.81 (3H, s), 3.55 (1H, br d, J=9.4 Hz), 3.00 (3H, s),2.90 (3H, s).

(45g) 7-{[(5-Chloro-2-methoxyphenyl)sulfonyl]amino}-N,N-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-3-carboxamide

The title compound (261.1 mg, yield for 2 steps: 69%) was obtained byproduction according to the method described in Examples (1d) and (9)using7-amino-4-(2,4-dimethoxybenzyl)-N,N-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-3-carboxamide(340.2 mg, 0.82 mmol) obtained in Example (45f) and5-Chloro-2-methoxybenzenesulfonyl chloride (207.3 mg, 0.86 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.40 (1H, d, J=2.7 Hz), 8.14 (1H, d,J=2.7 Hz), 7.74 (1H, d, J=2.7 Hz), 7.48 (1H, dd, J=9.0, 2.7 Hz), 7.34(1H, br s), 7.12 (1H, br s), 7.01 (1H, d, J=9.0 Hz), 4.72 (1H, br d,J=12.5 Hz), 4.56 (1H, br dd, J=6.6, 3.5 Hz), 4.27 (1H, dd, J=12.5, 6.6Hz), 4.08 (3H, s), 3.11 (3H, s), 3.05 (3H, s).

MS spectrum (ES/APCI⁺): 455 (M+H), 457 (M+2+H).

Example 465-chloro-2-methoxy-N-[3-(morpholin-4-ylcarbonyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

(46a)2-[(2,4-Dimethoxybenzyl)amino]-3-hydroxy-1-(morpholin-4-yl)propan-1-one

The title compound (1.39 g, yield for 3 steps: 88%) was obtained byproduction according to the method described in Examples (45b), (45c)and (8a) using O-benzyl-N-[(benzyloxy)carbonyl]serine (1.50 g, 4.55mmol) obtained in example (45a), morpholine (0.96 mL, 11 mmol) and2,4-dimethoxybenzaldehyde (0.71 g, 4.3 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 7.11 (1H, d, J=8.2 Hz), 6.44-6.41(2H, m), 3.82 (3H, s), 3.80 (3H, s), 3.75 (1H, d, J=12.9 Hz), 3.68-3.51(9H, m), 3.44-3.39 (3H, m).

(46b)4-(2,4-Dimethoxybenzyl)-3-(morpholin-4-ylcarbonyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one

The title compound (0.87 g, yield for 2 steps: 45%) was obtained byproduction according to the method described in Examples (1a) and (35c)using 2-chloro-5-nitropyridine-3-carboxylic acid (0.85 g, 4.2 mmol) and2-[(2,4-dimethoxybenzyl)amino]-3-hydroxy-1-(morpholin-4-yl)propan-1-one(1.40 g, 4.3 mmol) obtained in Example (46a).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 9.75 (1H, d, J=2.7 Hz), 9.13 (1H, d,J=2.7 Hz), 7.33 (1H, d, J=8.2 Hz), 6.51-6.47 (2H, m), 4.99 (1H, d,J=14.1 Hz), 4.86-4.79 (2H, m), 4.53 (1H, d, J=14.1 Hz), 4.36 (1H, d,J=12.9 Hz), 3.83 (3H, s), 3.81 (3H, s), 3.74-3.29 (8H, m).

(46c)5-Chloro-2-methoxy-N-[3-(morpholin-4-ylcarbonyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide

The title compound (255.5 mg, yield for 3 steps: 28%) was obtained byproduction according to the method described in Examples (8d), (1d) and(9) using4-(2,4-dimethoxybenzyl)-3-(morpholin-4-ylcarbonyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(0.87 g, 1.8 mmol) obtained in Example (46b) and5-chloro-2-methoxybenzenesulfonyl chloride (0.32 g, 1.3 mmol).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 10.28 (1H, br s), 8.36 (1H, br d,J=5.5 Hz), 8.32 (1H, d, J=2.7 Hz), 8.03 (1H, d, J=2.7 Hz), 7.68-7.65(2H, m), 7.26 (1H, d, J=8.6 Hz), 4.76 (1H, t, J=5.5 Hz), 4.62 (1H, dd,J=12.9, 5.5 Hz), 4.33 (1H, d, J=12.5 Hz), 3.88 (3H, s), 3.60-3.37 (8H,m).

MS spectrum (ES/APCI⁺): 497 (M+H), 499 (M+2+H).

(Example 47) Potassium [(5-chloro-2-methoxyphenyl)sulfonyl](5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)azanide(potassium salt of Example 9)

(47a)5-Chloro-N-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide

To a mixture of7-amino-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(1.31 g, 3.98 mmol) obtained in Example (8d) and pyridine (20 mL, 249mmol), 5-chloro-2-methoxybenzenesulfonyl chloride (1.035 g, 4.29 mmol)was added at room temperature, and the mixture was stirred at 80° C. for2.5 hours in an oil bath. The reaction mixture was cooled and thenconcentrated under reduced pressure, and the residue was purified in anautomatic chromatography apparatus (ethyl acetate/methanol=100/0-85/15)to obtain the title compound (2.17 g, yield: quantitative).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.24 (1H, d, J=3.0 Hz), 8.07 (1H, d,J=3.0 Hz), 7.74 (1H, d, J=2.4 Hz), 7.48 (1H, dd, J=8.8, 2.7 Hz),7.30-7.22 (2H, m), 7.01 (1H, d, J=9.1 Hz), 6.49-6.46 (2H, m), 4.70 (2H,s), 4.32 (2H, t, J=4.6 Hz), 4.09 (3H, s), 3.81-3.80 (6H, m), 3.60 (2H,t, J=4.6 Hz).

(47b)5-Chloro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

To a suspension of5-chloro-N-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide(2.17 g, 4.06 mmol) obtained in Example (47a) in chloroform (30 mL),anisole (0.88 mL, 8.1 mmol), trifluoroacetic acid (15 mL, 195 mmol) andtrifluoromethanesulfonic acid (0.73 mL, 8.3 mmol) were added at roomtemperature, and the mixture was stirred at room temperature for 1 hour.The reaction mixture was concentrated under reduced pressure, and theconcentrated mixture was diluted by addition of chloroform and asaturated aqueous solution of sodium bicarbonate. The precipitated solidwas collected by filtration. An organic layer of the filtrate wasseparated, and dried over anhydrous sodium sulfate. After filtration,the solvent was distilled off under reduced pressure. The residue wascombined with the above precipitated solid, diisopropyl ether was addedthereto, and the suspension was stirred at room temperature for 1 hour.The precipitated solid was collected by filtration, and then dried toobtain the title compound (1.2921 g, yield: 83%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.29 (1H, br s), 8.53 (1H, br t,J=5.2 Hz), 8.11-8.08 (2H, m), 7.69-7.64 (2H, m), 7.26 (1H, d, J=8.5 Hz),4.37-4.35 (2H, m), 3.88 (3H, s), 3.38-3.34 (2H, m).

(47c) Potassium[(5-chloro-2-methoxyphenyl)sulfonyl](5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)azanide

To a suspension of5-chloro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide(1.0921 g, 2.845 mmol) obtained in Example (47b) in ethanol (12 mL), asolution of 0.5 N potassium hydroxide in ethanol (5.68 mL, 2.85 mmol)was added at room temperature, and the mixture was stirred at roomtemperature for 1 hour. The precipitated solid was collected byfiltration, washed with ethanol and then dried to obtain the titlecompound (1.1065 g, yield: 92%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.19 (1H, br t, J=5.2 Hz), 7.70(1H, br t, J=2.4 Hz), 7.65-7.61 (2H, m), 7.35-7.32 (1H, m), 6.99 (1H, d,J=9.1 Hz), 4.18 (2H, t, J=5.2 Hz), 3.70-3.62 (3H, m), 3.22 (2H, q, J=5.2Hz).

(Example 48) Potassium [(5-fluoro-2-methoxyphenyl)sulfonyl](5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)azanide(potassium salt of Example 10)

(48a)N-[4-(2,4-Dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide

To a mixture of7-amino-4-(2,4-dimethoxybenzyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(3.83 g, 11.2 mmol) obtained in Example (8d) and pyridine (18.1 mL, 223mmol), 5-fluoro-2-methoxybenzenesulfonyl chloride (2.76 g, 12.3 mmol)was added at room temperature, and the mixture was stirred at 80° C. for1 hour in an oil bath. The reaction mixture was cooled to roomtemperature, diluted with water (90 mL) to precipitate a solid, and thesuspension was stirred at room temperature for 1 hour. The precipitatedsolid was collected by filtration, and washed with water to obtain thecrude solid. A suspension of the crude solid in ethanol (60 mL) wasstirred at 80° C. for 1 hour in an oil bath. After cooling, thesuspension was stirred in an ice water bath for 30 minutes. Theprecipitated solid was collected by filtration, washed with coldethanol, and then dried to obtain the title compound (4.87 g, yield:84%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.34 (1H, br s), 8.09 (1H, d,J=2.7 Hz), 7.97 (1H, t, J=2.7 Hz), 7.52-7.47 (2H, m), 7.26-7.23 (1H, m),7.09 (1H, d, J=8.2 Hz), 6.58 (1H, d, J=2.7 Hz), 6.49 (1H, dd, J=8.2, 2.7Hz), 4.57 (2H, s), 4.28 (2H, br t, J=4.7 Hz), 3.86 (3H, s), 3.77 (3H,s), 3.75 (3H, s), 3.53 (2H, br t, J=4.7 Hz).

(48b)5-Fluoro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide

To a suspension ofN-[4-(2,4-dimethoxybenzyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide(4.86 g, 9.39 mmol) obtained in Example (48a) and anisole (2.04 mL, 18.8mmol) in chloroform (45 mL), trifluoroacetic acid (14.4 mL, 188 mmol)and trifluoromethanesulfonic acid (1.65 mL, 18.8 mmol) were added atroom temperature, and the mixture was stirred at room temperature for 30minutes. The reaction mixture was carefully poured into a suspension ofsodium bicarbonate (17.4 g, 207 mmol) in water (90 mL) at roomtemperature, and the mixture was stirred at room temperature for 10minutes. Most of the organic solvents were distilled off under reducedpressure, the concentrated mixture was diluted by addition of ethylacetate (90 mL), a precipitated solid was collected by filtration, andwashed with water and ethyl acetate to obtain the crude solid. To asuspension of the crude solid in ethanol (50 mL), a 1 N aqueous solutionof potassium hydroxide (10.3 mL, 10.3 mmol) was added at roomtemperature, and the mixture was stirred at room temperature for 10minutes. The reaction mixture was filtered, and the residue on thefilter paper was washed with water and ethanol. The filtrate andwashings were combined, a 1 N hydrochloric acid (10.3 mL, 10.3 mmol) wasadded thereto, and the suspension was stirred in an ice water bath for20 minutes. The precipitated solid was collected by filtration, washedwith cold ethanol, and then dried to obtain the slightly crude solid. Toa suspension of the slightly crude solid in ethanol (50 mL), a 1 Naqueous solution of potassium hydroxide (8.8 mL, 8.8 mmol) was added atroom temperature, and the mixture was stirred at room temperature for 30minutes. A 1 N hydrochloric acid (8.8 mL, 8.8 mmol) was added thereto,and the suspension was stirred at room temperature for 30 minutes. Theprecipitated solid was collected by filtration, washed with water andethanol, and then dried to obtain the title compound (2.16 g, yield:63%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.28 (1H, br s), 8.52 (1H, br t,J=4.9 Hz), 8.11-8.08 (2H, m), 7.51-7.46 (2H, m), 7.26-7.23 (1H, m), 4.36(2H, t, J=4.3 Hz), 3.86 (3H, s), 3.40-3.35 (2H, m).

(48c) Potassium[(5-fluoro-2-methoxyphenyl)sulfonyl](5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)azanide

To a suspension of5-Fluoro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide(1.950 g, 5.308 mmol) obtained in example (48b) in a mixed solvent ofethanol (53.5 mL) and water (0.478 mL), a solution of 0.5 N potassiumhydroxide in ethanol (11.15 mL, 5.574 mmol) was added at roomtemperature, and the mixture was stirred at room temperature for 2hours. The precipitated solid was collected by filtration, washed withethanol and then dried to obtain the title compound (2.200 g, yield:quantitative).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.19 (1H, br t, J=5.2 Hz), 7.72(1H, d, J=2.7 Hz), 7.63 (1H, d, J=2.7 Hz), 7.41 (1H, dd, J=9.0, 3.1 Hz),7.16-7.11 (1H, m), 6.98 (1H, dd, J=9.0, 4.3 Hz), 4.18 (2H, t, J=5.2 Hz),3.65 (3H, s), 3.23 (2H, q, J=5.2 Hz).

(Example 49) Sodium [(5-fluoro-2-methoxyphenyl)sulfonyl](5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)azanide(sodium salt of Example 10)

To a suspension of5-Fluoro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide(101.9 mg, 0.277 mmol) obtained in example (48b) in ethanol (2.7 mL), a2 N aqueous solution of sodium hydroxide (0.138 mL, 0.277 mmol) wasadded at room temperature, and the mixture was stirred at roomtemperature for 30 minutes. The precipitated solid was collected byfiltration, washed with ethanol and then dried to obtain the titlecompound (98.4 mg, yield: 91%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.20 (1H, br t, J=5.1 Hz), 7.71(1H, d, J=2.7 Hz), 7.62 (1H, d, J=2.7 Hz), 7.41 (1H, dd, J=9.0, 3.1 Hz),7.16-7.11 (1H, m), 6.97 (1H, dd, J=9.0, 4.3 Hz), 4.17 (2H, t, J=5.1 Hz),3.66 (3H, s), 3.22 (2H, q, J=5.1 Hz).

(Example 50) Potassium{[5-chloro-2-(trifluoromethoxy)phenyl]sulfonyl}(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)azanide(potassium salt of Example 13)

The title compound (85.2 mg, yield: 78%) was obtained by productionaccording to the method described in Example (47c) using5-chloro-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-(trifluoromethoxy)benzenesulfonamide(100 mg, 0.228 mmol) obtained in example (13c) and a solution of 0.5 Npotassium hydroxide in ethanol (0.478 mL, 0.240 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.22 (1H, br t, J=5.2 Hz),7.78-7.73 (2H, m), 7.63-7.62 (1H, m), 7.53-7.51 (1H, m), 7.36-7.33 (1H,m), 4.19 (2H, t, J=5.2 Hz), 3.23 (2H, q, J=5.2 Hz).

(Example 51) Potassium [(5-chloro-2-methoxyphenyl)sulfonyl][(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]azanide(potassium salt of Example 27)

The title compound (124.1 mg, yield: 94%) was obtained by productionaccording to the method described in Example (47c) using5-chloro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide(121.3 mg, 0.293 mmol) obtained in Example (27f) and a solution of 0.5 Npotassium hydroxide in ethanol (0.962 mL, 0.482 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 7.93 (1H, br s), 7.77 (1H, d,J=2.7 Hz), 7.70 (1H, d, J=2.7 Hz), 7.64 (1H, d, J=2.7 Hz), 7.34 (1H, dd,J=8.6, 2.7 Hz), 6.99 (1H, d, J=8.6 Hz), 4.92 (1H, br t, J=5.7 Hz),4.20-4.12 (2H, m), 3.66 (3H, s), 3.46-3.41 (3H, m).

(Example 52) Potassium[(5-fluoro-2-methoxyphenyl)sulfonyl][(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]azanide(potassium salt of Example 28)

The title compound (78.7 mg, yield: 84%) was obtained by productionaccording to the method described in Examples (47c) using5-fluoro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide (75.5 mg, 0.190 mmol)obtained in Example (28b) and a solution of 0.5 N potassium hydroxide inethanol (0.386 mL, 0.194 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 7.92 (1H, br s), 7.77 (1H, br s),7.71 (1H, d, J=2.7 Hz), 7.41 (1H, dd, J=9.0, 3.1 Hz), 7.16-7.11 (1H, m),6.97 (1H, dd, J=9.0, 4.3 Hz), 4.91 (1H, t, J=5.5 Hz), 4.20-4.12 (2H, m),3.65 (3H, s), 3.46-3.40 (3H, m).

(Example 53) Potassium[(5-bromo-2-methoxyphenyl)sulfonyl][(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]azanide(potassium salt of Example 29)

The title compound (92.7 mg, yield: 82%) was obtained by productionaccording to the method described in Example (47c) using5-bromo-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide(104.4 mg, 0.228 mmol) obtained in Example (29b) and a solution of 0.5 Npotassium hydroxide in ethanol (0.451 mL, 0.228 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 7.93 (1H, br d, J=3.5 Hz),7.78-7.75 (2H, m), 7.68 (1H, d, J=2.7 Hz), 7.44 (1H, dd, J=9.0, 2.7 Hz),6.93 (1H, d, J=9.0 Hz), 4.92 (1H, t, J=5.5 Hz), 4.20-4.14 (2H, m), 3.63(3H, s), 3.46-3.41 (3H, m).

(Example 54) Potassium{[5-chloro-2-(trifluoromethoxy)phenyl]sulfonyl}[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]azanide(potassium salt of Example 31)

The title compound (44 mg, yield: 58%) was obtained by productionaccording to the method described in Example (47c) using5-chloro-N-[(3S)-3-(hydroxymethyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-(trifluoromethoxy)benzenesulfonamide(70 mg, 0.15 mmol) obtained in Example (31b) and a solution of 0.5 Npotassium hydroxide in ethanol (0.31 mL, 0.16 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 7.96 (1H, br d, J=3.5 Hz), 7.78(1H, d, J=2.7 Hz), 7.77 (1H, d, J=2.7 Hz), 7.72 (1H, d, J=2.7 Hz), 7.51(1H, dd, J=8.6, 2.7 Hz), 7.34-7.32 (1H, m), 4.95-4.92 (1H, m), 4.21-4.14(2H, m), 3.43-3.39 (3H, m).

(Example 55) Potassium [(5-chloro-2-methoxyphenyl)sulfonyl](5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)azanide(potassium salt of Example 35)

(55a)5-Chloro-N-[4′-(2,4-dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-2-methoxybenzenesulfonamide

To a mixture of7′-amino-4′-(2,4-dimethoxybenzyl)spiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one (0.9040 g, 2.54 mmol) obtained in Example (35d) and pyridine(4.1 mL, 51 mmol), 5-chloro-2-methoxybenzenesulfonyl chloride (0.6450 g,2.68 mmol) was added at room temperature, and the mixture was stirred at80° C. for 20 minutes in an oil bath. The reaction mixture was cooledand then concentrated under reduced pressure, and the residue wasdiluted with water, followed by extraction with ethyl acetate. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride, and anhydrous magnesium sulfate and charcoal were addedthereto. After filtration through pad of Celite 545 (R), the solvent wasdistilled off under reduced pressure. To the residue, diisopropyl ether(7 mL) and ethyl acetate (7 mL) were added to precipitate a solid. Thesuspension was stirred at room temperature for 30 minutes. Theprecipitated solid was collected by filtration, washed with diisopropylether, and then dried to obtain the title compound (1.3007 g, yield:92%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.20 (1H, d, J=2.7 Hz), 7.84 (1H, d,J=2.7 Hz), 7.73 (1H, d, J=2.7 Hz), 7.47 (1H, dd, J=9.0, 2.7 Hz),7.16-7.14 (1H, m), 7.02-6.99 (2H, m), 6.46-6.43 (2H, m), 4.66 (2H, brs), 4.06 (3H, s), 3.93 (2H, br s), 3.81 (3H, s), 3.79 (3H, s), 0.88 (2H,br s), 0.64 (2H, br s).

(55b)5-Chloro-2-methoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide

To a mixture of5-chloro-N-[4′-(2,4-dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-2-methoxybenzenesulfonamide(1.2938 g, 2.31 mmol) obtained in Example (55a) and anisole (0.51 mL,4.7 mmol) in chloroform (11.5 mL), trifluoroacetic acid (3.60 mL, 47.0mmol) and trifluoromethanesulfonic acid (0.41 mL, 4.7 mmol) were addedunder ice cooling, and the mixture was stirred at the same temperatureas above for 3 hours and subsequently stirred at room temperature for 5hours. The reaction mixture was carefully poured into a suspension ofsodium bicarbonate (3.88 g, 46.2 mmol) in water (11.5 mL) at roomtemperature, and the mixture was stirred at room temperature for 1 hour.Most of the organic solvents were distilled off under reduced pressure,the concentrated mixture was diluted by addition of water (30 mL) andethyl acetate (30 mL), a precipitated solid was collected by filtration,and washed with water and ethyl acetate to obtain the crude solid. To asuspension of the crude solid in a mixed solvent of ethanol (11.5 mL)and water (11.5 mL), a 1 N aqueous solution of potassium hydroxide (3.45mL, 3.48 mmol) was added at room temperature, and the mixture wasstirred at room temperature for 10 minutes. After filtration, a 2 Nhydrochloric acid (1.74 mL, 3.49 mmol) was added to the filtrate, andthe precipitated solid was collected by filtration, washed with waterand ethanol, and then dried to obtain the title compound (0.6970 g,yield: 74%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.29 (1H, br s), 8.84 (1H, br s),8.08 (1H, d, J=3.1 Hz), 7.95 (1H, d, J=3.1 Hz), 7.67 (1H, dd, J=9.0, 2.7Hz), 7.63 (1H, d, J=2.7 Hz), 7.25 (1H, d, J=9.0 Hz), 4.26 (2H, s), 3.88(3H, s), 0.75-0.73 (4H, m).

(55c) Potassium[(5-chloro-2-methoxyphenyl)sulfonyl](5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)azanide

To a suspension of5-chloro-2-methoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide(40.0 mg, 0.098 mmol) obtained in Example (55b) in ethanol (2 mL), asolution of 0.5 N potassium hydroxide in ethanol (0.195 mL, 0.098 mmol)was added at room temperature, and the mixture was stirred at roomtemperature for 2 hours. The mixture was concentrated under reducedpressure, acetone (1 mL) was added thereto, the precipitated solid wascollected by filtration, washed with acetone, and then dried to obtainthe title compound (42 mg, yield: 96%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.48 (1H, br s), 7.68 (1H, d,J=2.7 Hz), 7.61 (1H, d, J=2.7 Hz), 7.54 (1H, d, J=2.7 Hz), 7.32 (1H, dd,J=8.6, 2.7 Hz), 6.98 (1H, d, J=8.6 Hz), 4.07 (2H, s), 3.65 (3H, s),0.68-0.60 (4H, m).

(Example 56) Sodium [(5-chloro-2-methoxyphenyl)sulfonyl](5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)azanide(sodium salt of Example 35)

To a suspension of5-chloro-2-methoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide(95.2 mg, 0.232 mmol) obtained in Example (55b) in ethanol (2.3 mL), a 2N aqueous solution of sodium hydroxide (0.116 mL, 0.233 mmol) was addedat room temperature, and the mixture was stirred at room temperature for15 minutes. The mixture was concentrated under reduced pressure, acetone(2.3 mL) was added thereto, the precipitated solid was collected byfiltration, washed with acetone, and then dried to obtain the titlecompound (106.2 mg, yield: quantitative).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.49 (1H, br s), 7.69 (1H, d,J=2.7 Hz), 7.62 (1H, d, J=2.7 Hz), 7.55 (1H, d, J=2.7 Hz), 7.33 (1H, dd,J=8.6, 2.7 Hz), 6.99 (1H, d, J=8.6 Hz), 4.07 (2H, s), 3.67 (3H, s),0.67-0.60 (4H, m).

(Example 57) Potassium [(5-fluoro-2-methoxyphenyl)sulfonyl](5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)azanide(potassium salt of Example 36)

The title compound (41 mg, yield: 94%) was obtained by productionaccording to the method described in Example (47c) using5-fluoro-2-methoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide(40.0 mg, 0.102 mmol) obtained in Example 36 and a solution of 0.5 Npotassium hydroxide in ethanol (0.203 mL, 0.102 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.48 (1H, br s), 7.68 (1H, d,J=2.7 Hz), 7.55 (1H, d, J=2.7 Hz), 7.39 (1H, dd, J=9.0, 3.1 Hz),7.15-7.10 (1H, m), 6.96 (1H, dd, J=9.0, 4.3 Hz), 4.06 (2H, br s), 3.64(3H, br s), 0.66-0.61 (4H, m).

(Example 58) Potassium{[5-chloro-2-(trifluoromethoxy)phenyl]sulfonyl}(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)azanide(potassium salt of Example 40)

The title compound (63 mg, yield: 94%) was obtained by productionaccording to the method described in Example (47c) using5-chloro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)-2-(trifluoromethoxy)benzenesulfonamide(62.0 mg, 0.134 mmol) obtained in Example (40c) and a solution of 0.5 Npotassium hydroxide in ethanol (0.267 mL, 0.134 mmol).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.51 (1H, br s), 7.76-7.72 (2H,m), 7.56-7.51 (2H, m), 7.35 (1H, d, J=9.0 Hz), 4.08 (2H, br s),0.65-0.63 (4H, m).

(Example 59) Potassium(2-ethoxy-5-fluorophenyl)sulfonyl](5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)azanide(potassium salt of Example 42)

(59a)N-[4′-(2,4-Dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-2-ethoxy-5-fluorobenzenesulfonamide

To a mixture of7′-amino-4′-(2,4-dimethoxybenzyl)spiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-5′(4′H)-one(0.9073 g, 2.55 mmol) obtained in Example (35d) and pyridine (4.1 mL, 51mmol), 5-fluoro-2-ethoxybenzenesulfonyl chloride (0.6401 g, 2.68 mmol)obtained in Example (42a) was added at room temperature, and the mixturewas stirred at 80° C. for 20 minutes in an oil bath. The reactionmixture was cooled and then concentrated under reduced pressure, and theresidue was diluted with water (50 mL) and ethyl acetate (50 mL), theaqueous layer was separated off, the organic layer was diluted withtetrahydrofuran (150 mL), and anhydrous magnesium sulfate and charcoalwere added thereto. After filtration through pad of Celite 545 (R), thesolvent was distilled off under reduced pressure. To the residue, ethylacetate (14 mL) was added to precipitate a solid, and the suspension wasstirred at room temperature for 1 hour. The precipitated solid wascollected by filtration, washed with ethyl acetate, and then dried toobtain the title compound (1.2525 g, yield: 88%).

¹H NMR spectrum (CDCl₃, 400 MHz) δ: 8.20 (1H, d, J=2.7 Hz), 7.85 (1H, d,J=2.7 Hz), 7.47 (1H, dd, J=7.4, 3.1 Hz), 7.23-7.14 (2H, m), 7.02-6.95(2H, m), 6.46-6.43 (2H, m), 4.66 (2H, br s), 4.29 (2H, q, J=7.0 Hz),3.92 (2H, br s), 3.80 (3H, s), 3.79 (3H, s), 1.58 (3H, t, J=7.0 Hz),0.87 (2H, br s), 0.63 (2H, br s).

(59b)2-Ethoxy-5-fluoro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide

To a mixture ofN-[4′-(2,4-dimethoxybenzyl)-5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl]-2-ethoxy-5-fluorobenzenesulfonamide(1.2658 g, 2.27 mmol) obtained in Example (59a) and anisole (0.50 mL,4.6 mmol) in chloroform (11.5 mL), trifluoroacetic acid (3.45 mL, 45.1mmol) and trifluoromethanesulfonic acid (0.40 mL, 4.0 mmol) were addedunder ice cooling, and the mixture was stirred at the same temperatureas above for 30 minutes and subsequently stirred at room temperature for5 hours. The reaction mixture was carefully poured into a suspension ofsodium bicarbonate (3.82 g, 45.5 mmol) in water (11.5 mL) at roomtemperature, isopropyl alcohol (5 mL) was added thereto, and the mixturewas stirred at room temperature for 20 minutes. Most of the organicsolvents were distilled off under reduced pressure, the concentratedmixture was diluted by addition of water (50 mL) followed by extractionwith a mixed solvent of ethyl acetate (100 mL) and tetrahydrofuran (50mL). The organic layer was washed with a saturated aqueous solution ofsodium chloride, and anhydrous magnesium sulfate and charcoal were addedthereto. After filtration through pad of Celite 545 (R), the solvent wasdistilled off under reduced pressure. To the residue, ethyl acetate (12mL) was added to precipitate a solid, and the suspension was stirred atroom temperature for 30 minutes. The precipitated solid was collected byfiltration, washed with ethyl acetate, and then dried to obtain thetitle compound (0.7940 g, yield: 86%).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 10.15 (1H, s), 8.83 (1H, s), 8.09(1H, d, J=2.7 Hz), 7.95 (1H, d, J=2.7 Hz), 7.52-7.44 (2H, m), 7.24 (1H,dd, J=9.0, 4.3 Hz), 4.26 (br 2H, s), 4.16 (2H, q, J=7.0 Hz), 1.26 (3H,t, J=7.0 Hz), 0.77-0.71 (4H, m).

(59c) Potassium[(2-ethoxy-5-fluorophenyl)sulfonyl](5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)azanide

To a suspension of2-ethoxy-5-fluoro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide(70.0 mg, 0.172 mmol) obtained in example (59b) in ethanol (5 mL), asolution of 0.5 N potassium hydroxide in ethanol (0.343 mL, 0.172 mmol)was added at room temperature, and the mixture was stirred at roomtemperature for 3 hours. The solvent was distillated off under reducepressure to obtain the title compound (77 mg, yield: quantitative).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.45 (1H, br s), 7.70 (1H, d,J=2.7 Hz), 7.54 (1H, d, J=2.7 Hz), 7.41 (1H, dd, J=9.0, 3.1 Hz),7.11-7.06 (1H, m), 6.95 (1H, dd, J=9.0, 4.3 Hz), 4.06 (2H, s), 3.93 (2H,q, J=6.9 Hz), 1.12 (3H, t, J=6.9 Hz), 0.67-0.59 (4H, m).

(Example 60) Sodium[(2-ethoxy-5-fluorophenyl)sulfonyl](5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)azanide(sodium salt of Example 42)

To a suspension of2-ethoxy-5-fluoro-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide(97.3 mg, 0.239 mmol) obtained in example (59b) in ethanol (2.4 mL), a 2N aqueous solution of sodium hydroxide (0.119 mL, 0.239 mmol) was addedat room temperature, and the mixture was stirred at room temperature for15 minutes. The mixture was concentrated under reduced pressure, acetone(2.4 mL) was added thereto, the precipitated solid was collected byfiltration, washed with acetone, and then dried to obtain the titlecompound (104.1 mg, yield: quantitative).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.47 (1H, br s), 7.71 (1H, d,J=2.7 Hz), 7.55 (1H, d, J=2.7 Hz), 7.41 (1H, dd, J=9.0, 3.1 Hz),7.13-7.07 (1H, m), 6.96 (1H, dd, J=9.0, 4.3 Hz), 4.06 (2H, s), 3.94 (2H,q, J=7.0 Hz), 1.13 (3H, t, J=7.0 Hz), 0.66-0.59 (4H, m).

(Example 61) Potassium [(2,5-dimethoxyphenyl)sulfonyl](5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)azanide(potassium salt of Example 43)

To a suspension of2,5-dimethoxy-N-(5′-oxo-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[3,2-f][1,4]oxazepin]-7′-yl)benzenesulfonamide(43.0 mg, 0.106 mmol) obtained in Example (43b) in ethanol (5 mL), asolution of 0.5 N potassium hydroxide in ethanol (0.211 mL, 0.106 mmol)was added at room temperature, and the mixture was stirred at roomtemperature for 2 hours. The solvent was distilled off under reducepressure to obtain the title compound (51 mg, yield: quantitative).

¹H NMR spectrum (DMSO-d6, 400 MHz) δ: 8.47 (1H, br s), 7.68 (1H, d,J=2.7 Hz), 7.55 (1H, d, J=2.7 Hz), 7.29 (1H, d, J=3.1 Hz), 6.89 (1H, d,J=8.6 Hz), 6.84 (1H, dd, J=8.6, 3.1 Hz), 4.05 (2H, br s), 3.66 (3H, s),3.63 (3H, s), 0.67-0.57 (4H, m).

TEST EXAMPLES (Test Example 1) Inhibitory Test of TNAP Activity

COS1 cells (DS Pharma Biomedical Co., Ltd.) were transfected with humanTNAP (OriGene Technologies, Inc.) using Lipofectamine LTX & Plus reagent(Invitrogen Corp.). On the next day, the medium was replaced with afresh medium, and the cells were cultured in an incubator for 3 days.After 3 days, the culture supernatant was collected and concentrated bycentrifugation at 5000 G for 30 minutes using Amicon 14, 10⁴ cut (MerckMillipore). The concentrated culture supernatant was dialyzed against 5L of 50 mM Tris/200 mM NaCl/1 mM MgCl₂/20 μM ZnCl₂ twice and used as anenzyme source (enzyme solution). The substrate pNPP (ProteoChem Inc.)was adjusted to 3.1 mM with Milli-Q water, and a solution of each testcompound dissolved in dimethyl sulfoxide (DMSO; Wako Pure ChemicalIndustries, Ltd.) by 6 serial dilutions at a 5-fold common ratio from100 μM, or DMSO was added thereto at a final concentration of 1% byvolume. The enzyme solution adjusted to 2 μg/mL with an assay buffer(200 mM Tris/2 mM MgCl₂/0.04 mM ZnCl₂/0.01% Tween 20) was added in thesame amount of the substrate solution and incubated at room temperaturefor 60 minutes. Then, the absorbance (ABS: 405 nm) was measured using amicroplate reader (model plus 384, Molecular Devices, LLC), and theconcentration of produced p-nitrophenol was calculated. The inhibitionof human TNAP activity by the test compound was evaluated on the basisof the concentration IC₅₀ at which each test compound suppressed 50% ofp-nitrophenol production.

The results are shown in Table 1. [Table 1]

TABLE 1 Example compound No. IC₅₀ (nM) 1 6.3 2 12.7 3 12.8 4 22.9 5 71.36 6.1 7 10.7 8 9.1 9 1.4 10 4.0 11 4.8 12 13.4 13 3.4 14 36.2 15 95.7 166.2 17 12.6 18 3.9 19 6.4 20 27.1 21 46.0 22 1.7 23 3.5 24 7.2 25 1.7 268.7 27 1.5 28 3.6 29 1.2 30 3.8 31 1.6 32 4.1 33 1.9 34 6.7 35 1.1 362.2 37 43.4 38 24.4 39 13.2 40 1.9 41 2.7 42 0.6 43 1.0 44 1.4 45 14.646 25.2

The compound of the present invention exhibits the excellent inhibitionof human TNAP activity and is useful as a pharmaceutical agent for thetreatment or prophylaxis of ectopic calcification.

(Test Example 2) Specific Inhibitory Test of TNAP Activity

COS1 cells (DS Pharma Biomedical Co., Ltd.) were transfected with humanIAP (small-intestinal alkaline phosphatase, purchased from OriGeneTechnologies, Inc.) or human PLAP (placental alkaline phosphatase,purchased from OriGene Technologies, Inc.) using Lipofectamine LTX &Plus reagent (Invitrogen Corp.). On the next day, the medium wasreplaced with a fresh medium, and the cells were cultured in anincubator for 3 days. After 3 days, the culture supernatant wascollected and concentrated by centrifugation at 5000 G for 30 minutesusing Amicon 14, 10⁴ cut (Merck Millipore). The concentrated culturesupernatant was dialyzed against 5 L of 50 mM Tris/200 mM NaCl/1 mMMgCl₂/20 μM ZnCl₂ twice and used as an enzyme source (enzyme solution).The substrate pNPP (ProteoChem Inc.) was adjusted to 3.1 mM with Milli-Qwater, and a solution of each test compound dissolved in dimethylsulfoxide (DMSO; Wako Pure Chemical Industries, Ltd.) by 6 serialdilutions at a 5-fold common ratio from 100 μM, or DMSO was addedthereto at a final concentration of 1% by volume. The enzyme solution ofhuman IAP or human PLAP adjusted to 2 μg/mL with an assay buffer (200 mMTris/2 mM MgCl₂/0.04 mM ZnCl₂/0.01% Tween 20) was added in the sameamount of the substrate solution and incubated at room temperature for60 minutes. Then, the absorbance (ABS: 405 nm) was measured using amicroplate reader (model plus 384, Molecular Devices, LLC), and theconcentration of produced p-nitrophenol was calculated. The inhibitionof human IAP or PLAP activity by the test compound was evaluated on thebasis of the concentration IC₅₀ at which each test compound suppressed50% of p-nitrophenol production.

The compound of the present invention exhibits the excellent specificinhibition of TNAP activity and is useful as a pharmaceutical drug forthe treatment or prevention of ectopic calcification.

(Test Example 3) Inhibitory Test of Plasma TNAP Activity in B6 Mouse(Charles River Laboratories Japan, Inc.)

After blood sampling from the tail vein using a heparin-treatedhematocrit capillary tube (EM Meister Hematocrit Capillary Tube, AS ONECorp.) (as the sample before compound administration), each testcompound suspended in a 0.5% methylcellulose solution (powder purchasedfrom Wako Pure Chemical Industries, Ltd. was adjusted to 0.5% withOtsuka distilled water) was administered orally to the mouse. 1, 2, 4,6, and 24 hours after the administration, blood was collected from thetail vein using a heparin-treated hematocrit capillary tube to obtain aplasma sample. The plasma sample was added to an assay buffer (1 M Tris,1 M MgCl₂, 20 mM ZnCl₂, and water, pH 7.5), and the mixture was leftstanding for 5 minutes. Then, the absorbance at 405 nm was measured andused as a blank. The substrate pNPP was added to the plasma sample andincubated at room temperature for 180 minutes. Then, the absorbance(ABS: 405 nm) was measured using a microplate reader (model plus 384,Molecular Devices, LLC), and the concentration of produced p-nitrophenolwas calculated. The blank was subtracted from all measurement values tocalculate TNAP activity at each time point with the TNAP activity of thesample before compound administration defined as 100%. Thepharmaceutical effect of the test compound was evaluated by the averageinhibition of plasma ALP (80-90% containing TNAP) activity for 6 hoursfrom 0 hour to 6 hours after the administration of the test compound. Itwas calculated according to the following expression: 100−((plasma ALPactivity at 0 hr+plasma ALP activity at 1 hr)*½+(plasma ALP activity at1 hr+plasma ALP activity at 2 hr)*½+(plasma ALP activity at 2 hr+plasmaALP activity at 4 hr)*2/2+(plasma ALP activity at 4 hr+plasma ALPactivity at 6 hr)*2/2)/6.

The results are shown in Table 2.

TABLE 2 Plasma ALP inhibition (6h ave. Example compound No. inhibition%) 47 54.7 48 61.6 50 56.0 51 63.7 52 61.3 53 59.2 54 74.8 55 58.9 5753.5 58 50.3 59 66.2 61 67.5

The compound of the present invention exhibits an excellent in vivo TNAPinhibitory effect and is useful as a pharmaceutical agent for thetreatment or prophylaxis of ectopic calcification.

(Test Example 4) In Vivo Anti-Calcification Test in Vitamin D-InducedCalcification Model

A DBA/2 mouse (male, 6 weeks old when used, Charles River LaboratoriesJapan, Inc.) was given powder feed (FR-2 powder feed, Funabashi FarmCo., Ltd.) containing each test compound. 3.75 mg/kg cholecalciferol(Sigma-Aldrich Corp.) was intraperitoneally administered for 3 days fromthe next day. Seven days after the final cholecalciferol administration,the animal was sacrificed, and the thoracic aorta and the kidney weresampled. The tissue samples were freeze-dried (FREEZE DRYER, FRD-50M,Iwaki Asahi Techno Glass Corp.). Then, 10% formic acid (undilutedsolution purchased from Kishida Chemical Co., Ltd. was adjusted to 10%with Milli-Q water) was added to each tissue sample, which was thenhomogenized using QIAGEN Retsch MM300 TissueLyser (Qiagen N.V.). Thehomogenate was centrifuged, and the supernatant was used as a sample.The calcium concentration in the sample was measured as absorbance (ABS612 nm, Microplate reader, model plus 384, Molecular Devices, LLC) usingCalcium assay kit (Wako Pure Chemical Industries, Ltd.) to calculate theamount of calcium in the tissue.

The compound of the present invention exhibits an excellentanti-calcification effect and is useful as a therapeutic agent for thetreatment or prevention of ectopic calcification.

(Test Example 5) In Vivo Anti-Calcification Test in Nephrectomized Mouse

A 5/6 nephrectomized DBA/2 mouse (male, 8 weeks old) was purchased fromCLEA Japan, Inc. This mouse was loaded with 1.2% high-phosphorus diet(Oriental Yeast Co., Ltd.). Each test compound suspended in a 0.5%methylcellulose solution (powder purchased from Wako Pure ChemicalIndustries, Ltd. was adjusted to 0.5% with Otsuka distilled water) wasadministered orally twice daily for three months. After three months,the animal was sacrificed, and the kidney was sampled. The tissue samplewas freeze-dried (FREEZE DRYER, FRD-50M, Iwaki Asahi Techno GlassCorp.). Then, 10% formic acid (undiluted solution purchased from KishidaChemical Co., Ltd. was adjusted to 10% with Milli-Q water) was added tothe tissue sample, which was then homogenized using QIAGEN Retsch MM300TissueLyser (Qiagen N.V.). The homogenate was centrifuged, and thesupernatant was used as a sample. The calcium concentration in thesample was measured as absorbance (ABS 612 nm, Microplate reader, modelplus 384, Molecular Devices, LLC) using Calcium assay kit (Wako PureChemical Industries, Ltd.) to calculate the amount of calcium in thetissue.

The compound of the present invention exhibits an excellentanti-calcification effect and is useful as a pharmaceutical drug for thetreatment or prophylaxis of ectopic calcification.

(Test Example 6) Pharmacokinetic Test

The pharmacokinetic test can be conducted according to a methodwell-known in the field of pharmacodynamics.

Each test compound was suspended in a 0.5% aqueous methylcellulosesolution. The obtained suspension was orally administered at a dose inan appropriate range (e.g., 0.01 mg/kg to 10 mg/kg) to an animal (e.g.,a mouse, a rat, a dog, or a cynomolgus monkey) generally used in thepharmacokinetic test. Also, the test compound was dissolved in saline.The obtained solution was intravenously (e.g., through the tail vein,the cephalic vein, or the saphenous vein) administered at a dose in anappropriate range (e.g., 0.1 mg/kg to 10 mg/kg) to an animal (e.g., amouse, a rat, a dog, or a cynomolgus monkey) generally used in thepharmacokinetic test. After given times (e.g., 0.08, 0.25, 0.5, 1, 2, 4,6, 8, and 24 hours) from the administration, blood was collected from anappropriate blood collection site (e.g., the jugular vein, the cephalicvein, or the saphenous vein). The obtained blood was centrifuged toprepare a plasma sample. The concentration of the test compoundcontained in the plasma sample was measured by quantitative analysisusing a liquid chromatography-mass spectrometer (LC-MS/MS).

The pharmacokinetics of the test compound were evaluated on the basis ofmaximum plasma concentration (Cmax), area under the plasma drugconcentration-time curve (AUC), total clearance (CL), andbioavailability and analyzed using software (Phoenix, etc.). Cmaxrepresents the maximum plasma concentration of the orally administeredtest compound. AUC was calculated according to the trapezium rule fromthe plasma concentrations of the test compound from the time when thetest compound was administered up to the final time when the testcompound was quantifiable. The bioavailability was calculated accordingto the following expression:[(AUC after oral administration/Dose of the oral administration)/(AUCafter intravenous administration/Dose of the intravenousadministration)].

The compound of the present invention exhibits excellentpharmacokinetics (Cmax, AUC, CL, or bioavailability) and is useful as apharmaceutical (particularly, a pharmaceutical for the treatment orprevention of ectopic calcification).

PREPARATION EXAMPLES (Preparation Example 1) Capsule

Compound of Example 1  50 mg Lactose 128 mg Corn starch  70 mg Magnesiumstearate  2 mg 250 mg

A powder having the formulation mentioned above is mixed and siftedthrough a 60-mesh sieve. Then, this powder is put in a gelatin capsuleshell to prepare a capsule.

(Preparation Example 2) Tablet

Compound of Example 1  50 mg Lactose 126 mg Corn starch  23 mg Magnesiumstearate  1 mg 200 mg

A powder having the formulation mentioned above is mixed, granulatedusing corn starch paste, and dried, followed by compression in atableting machine to prepare tablets (200 mg each). This tablet can becoated, if necessary.

The novel pyridine compound represented by the general formula (I) ofthe present invention or the pharmacologically acceptable salt thereofhas an excellent TNAP inhibitory effect and is useful as apharmaceutical.

What is claimed is:
 1. A compound represented by the following formula

wherein R¹ represents a hydrogen atom, a C1-6 alkyl group (wherein thealkyl group is optionally substituted by one to three groups, which maybe the same or different, selected from the following substituents: ahydroxy group, a C1-6 alkoxy group optionally substituted by one tothree groups, which may be the same or different halogeno groups, anamino group optionally substituted by one or two groups, which may bethe same or different C1-6 alkyl groups, a C6-10 aryl group optionallysubstituted by one or two groups selected from substituent group A^(B),a 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur and optionally substituted by one or two groupsselected from substituent group A^(B), a carboxyl group, a C1-6alkylcarbonyl group, a C1-6 alkoxycarbonyl group, an aminocarbonyl groupoptionally substituted by one or two groups, which may be the same ordifferent C1-6 alkyl groups, a 4- to 7-membered saturatedheterocyclylcarbonyl group containing one or two heteroatoms, which maybe the same or different, selected from nitrogen, oxygen, and sulfur, anaminocarbonyloxy group optionally substituted by one or two groups,which may be the same or different C1-6 alkyl groups, a 4- to 7-memberedsaturated heterocyclylcarbonyloxy group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur), a C3-8 cycloalkyl group (wherein the cycloalkylgroup is optionally substituted by one to three groups, which may be thesame or different, selected from the following substituents: a hydroxygroup, a C1-6 alkoxy group optionally substituted by one to threegroups, which may be the same or different halogeno groups, a C3-8cycloalkyl group optionally substituted by one to three groups, whichmay be the same or different halogeno groups, a C6-10 aryl groupoptionally substituted by one or two groups, which may be the same ordifferent halogeno groups, a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur and optionally substituted byone or two groups, which may be the same or different halogeno groups, acarboxyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonyl group,an aminocarbonyl group optionally substituted by one or two groups,which may be the same or different C1-6 alkyl groups, a 4- to 7-memberedsaturated heterocyclylcarbonyl group containing one or two heteroatoms,which may be the same or different, selected from nitrogen, oxygen, andsulfur, an aminocarbonyloxy group optionally substituted by one or twogroups, which may be the same or different C1-6 alkyl groups, a 4- to7-membered saturated heterocyclylcarbonyloxy group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur, a halogeno group, and a cyano group), a C6-10 arylgroup (wherein the aryl group is optionally substituted by one or twogroups, which may be the same or different, selected from the followingsubstituents: a hydroxy group, a C1-6 alkyl group optionally substitutedby one to three groups, which may be the same or different halogenogroups, a C3-8 cycloalkyl group optionally substituted by one to threegroups, which may be the same or different halogeno groups, a C1-6alkoxy group optionally substituted by one to three groups, which may bethe same or different halogeno groups, a C6-10 aryl group optionallysubstituted by one group selected from substituent group A^(B), a 3- to10-membered heterocyclyl group containing one to four heteroatoms, whichmay be the same or different, selected from nitrogen, oxygen, and sulfurand optionally substituted by one group selected from substituent groupA^(B), a carboxyl group, an amino group optionally substituted by one ortwo groups, which may be the same or different C1-6 alkyl groups, a C1-6alkoxycarbonyl group, an aminocarbonyl group optionally substituted byone or two groups, which may be the same or different C1-6 alkyl groups,a 4- to 7-membered saturated heterocyclylcarbonyl group containing oneor two heteroatoms, which may be the same or different, selected fromnitrogen, oxygen, and sulfur, an aminocarbonyloxy group optionallysubstituted by one or two groups, which may be the same or differentC1-6 alkyl groups, a 4- to 7-membered saturated heterocyclylcarbonyloxygroup containing one or two heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur, a halogeno group,and a cyano group), or a 3- to 10-membered heterocyclyl group containingone to four heteroatoms, which may be the same or different, selectedfrom nitrogen, oxygen, and sulfur (wherein the heterocyclyl group isoptionally substituted by one or two groups, which may be the same ordifferent groups selected from the following substituents: a hydroxygroup, a C1-6 alkyl group optionally substituted by one to three groups,which may be the same or different halogeno groups, a C3-8 cycloalkylgroup optionally substituted by one to three groups, which may be thesame or different halogeno groups, a C1-6 alkoxy group optionallysubstituted by one to three groups, which may be the same or differenthalogeno groups, a C6-10 aryl group, a 3- to 10-membered heterocyclylgroup containing one to four heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur, a carboxyl group,an amino group, an aminocarbonyl group optionally substituted by one ortwo groups, which may be the same or different C1-6 alkyl groups, a 4-to 7-membered saturated heterocyclylcarbonyl group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur, an aminocarbonyloxy group optionally substituted byone or two groups, which may be the same or different C1-6 alkyl groups,a 4- to 7-membered saturated heterocyclylcarbonyloxy group containingone or two heteroatoms, which may be the same or different, selectedfrom nitrogen, oxygen, and sulfur, a halogeno group, and a cyano group),R² and R³ are the same or different and each represent a hydrogen atom,a C1-6 alkyl group (wherein the alkyl group is optionally substituted byone to three groups, which may be the same or different, selected fromthe following substituents: a hydroxy group, a C1-6 alkoxy groupoptionally substituted by one group selected from substituent groupA^(C), a C3-8 cycloalkyl group optionally substituted by one groupselected from substituent group A^(B), a C6-10 aryl group optionallysubstituted by one or two groups selected from substituent group A^(B),a 3- to 10-membered heterocyclyl group containing one to fourheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur and optionally substituted by one or two groupsselected from substituent group A^(B), a carboxyl group, a C1-6alkylcarbonyl group, a C1-6 alkoxycarbonyl group, an amino groupoptionally substituted by one or two groups, which may be the same ordifferent C1-6 alkyl groups, an aminocarbonyl group optionallysubstituted by one or two groups, which may be the same or differentC1-6 alkyl groups, a 4- to 7-membered saturated heterocyclylcarbonylgroup containing one or two heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur, anaminocarbonyloxy group optionally substituted by one or two groups,which may be the same or different C1-6 alkyl groups, a 4- to 7-memberedsaturated heterocyclylcarbonyloxy group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur, a halogeno group, and a cyano group), a C6-10 arylgroup (wherein the aryl group is optionally substituted by one or twogroups, which may be the same or different, selected from the followingsubstituents: a hydroxy group, a C1-6 alkoxy group optionallysubstituted by one to three groups, which may be the same or differenthalogeno groups, a C1-6 alkyl group optionally substituted by one groupselected from substituent group A^(D), a C3-8 cycloalkyl groupoptionally substituted by one group selected from substituent groupA^(D), a C6-10 aryl group optionally substituted by one group selectedfrom substituent group A^(D), a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur and optionally substituted byone group selected from substituent group A^(D), an amino groupoptionally substituted by one or two groups, which may be the same ordifferent C1-6 alkyl groups, a carboxyl group, a C1-6 alkylcarbonylgroup, a C1-6 alkoxycarbonyl group, an aminocarbonyl group optionallysubstituted by one or two groups, which may be the same or differentC1-6 alkyl groups, a 4- to 7-membered saturated heterocyclylcarbonylgroup containing one or two heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur, anaminocarbonyloxy group optionally substituted by one or two groups,which may be the same or different C1-6 alkyl groups, a 4- to 7-memberedsaturated heterocyclylcarbonyloxy group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur, a halogeno group, and a cyano group), a 3- to10-membered heterocyclyl group containing one to four heteroatoms, whichmay be the same or different, selected from nitrogen, oxygen, and sulfur(wherein the heterocyclyl group is optionally substituted by one or twogroups, which may be the same or different, selected from the followingsubstituents: a hydroxy group, a C1-6 alkoxy group optionallysubstituted by one to three groups, which may be the same or differenthalogeno groups, a C1-6 alkyl group optionally substituted by one groupselected from substituent group A^(D), a C3-8 cycloalkyl groupoptionally substituted by one group selected from substituent groupA^(D), a C6-10 aryl group optionally substituted by one group selectedfrom substituent group A^(D), a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur and optionally substituted byone group selected from substituent group A^(D), an amino groupoptionally substituted by one or two groups, which may be the same ordifferent C1-6 alkyl groups, a carboxyl group, a C1-6 alkylcarbonylgroup, a C1-6 alkoxycarbonyl group, an aminocarbonyl group optionallysubstituted by one or two groups, which may be the same or differentC1-6 alkyl groups, a 4- to 7-membered saturated heterocyclylcarbonylgroup containing one or two heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur, anaminocarbonyloxy group optionally substituted by one or two groups,which may be the same or different C1-6 alkyl groups, a 4- to 7-memberedsaturated heterocyclylcarbonyloxy group containing one or twoheteroatoms, which may be the same or different, selected from nitrogen,oxygen, and sulfur, a halogeno group, and a cyano group), a C1-6alkylcarbonyl group (wherein the alkylcarbonyl group is optionallysubstituted by one to three groups, which may be the same or different,selected from substituent group A^(E)), a C6-10 arylcarbonyl group(wherein the arylcarbonyl group is optionally substituted by one or twogroups, which may be the same or different, selected from substituentgroup A^(E) and a C1-6 halogenoalkyl group), a 3- to 10-memberedheterocyclylcarbonyl group containing one to four heteroatoms, which maybe the same or different, selected from nitrogen, oxygen, and sulfur(wherein the heterocyclylcarbonyl group is optionally substituted by oneor two groups, which may be the same or different, selected fromsubstituent group A^(E) and a C1-6 halogenoalkyl group), a carboxylgroup, a C1-6 alkoxycarbonyl group (wherein the alkoxycarbonyl group isoptionally substituted by one to three groups, which may be the same ordifferent, selected from substituent group A^(F)), an aminocarbonylgroup (wherein the aminocarbonyl group is optionally substituted by oneor two groups, which may be the same or different C1-6 alkyl groups eachoptionally substituted by one to three groups, which may be the same ordifferent, selected from substituent group A^(F)), a C6-10arylaminocarbonyl group (wherein the arylaminocarbonyl group isoptionally substituted by one or two groups, which may be the same ordifferent, selected from substituent group A^(E) and a C1-6halogenoalkyl group), a 4- to 7-membered saturated heterocyclylcarbonylgroup containing one or two heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur (wherein theheterocyclylcarbonyl group is optionally substituted by one to threegroups, which may be the same or different, selected from substituentgroup A^(F)), or a 3- to 10-membered heterocyclylaminocarbonyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur (wherein theheterocyclylaminocarbonyl group is optionally substituted by one or twogroups, which may be the same or different, selected from substituentgroup A^(E) and a C1-6 halogenoalkyl group), or the C1-6 alkyl groups ofR² and R³ are optionally bonded to each other to form a 3- to 6-memberedsaturated carbocyclic ring or to form a 4- to 6-membered saturatedheterocyclic ring via one nitrogen or oxygen atom (wherein one nitrogenatom in the 4- to 6-membered saturated heterocyclic ring is optionallyreplaced with a hydrogen atom, a C1-6 alkyl group, a C1-6 alkylcarbonylgroup, a C1-6 alkoxycarbonyl group), R⁴ and R⁵ are the same or differentand each represent a hydrogen atom, a C1-6 alkyl group (wherein thealkyl group is optionally substituted by one to three groups, which maybe the same or different, selected from substituent group A^(G)), aC6-10 aryl group (wherein the aryl group is optionally substituted byone or two groups, which may be the same or different, selected fromsubstituent group A^(G)), or a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur (wherein the heterocyclylgroup is optionally substituted by one or two groups, which may be thesame or different, selected from substituent group A^(G)), R⁶ representsa hydrogen atom, hydroxyl group or a C1-6 alkyl group (R⁶ is a carbonsubstituent of the pyridinyl ring, not a nitrogen substituent), eachsubstituent R⁷ may be the same or different and may each represent aC1-6 alkyl group (wherein the alkyl group is optionally substituted byone to three groups, which may be the same or different, selected fromsubstituent group A^(H)), a C1-6 alkoxy group (wherein the alkoxy groupis optionally substituted by one to three groups, which may be the sameor different, selected from substituent group A^(H)), a halogeno group,a C6-10 aryl group (wherein the aryl group is optionally substituted byone or two groups, which may be the same or different, selected fromsubstituent group A^(G)), a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur (wherein the heterocyclylgroup is optionally substituted by one or two groups, which may be thesame or different, selected from substituent group A^(G)), a hydroxygroup, an amino group (wherein the amino group is optionally substitutedby one or two groups, which may be the same or different C1-6 alkylgroups each optionally substituted by one to three groups, which may bethe same or different, selected from substituent group A^(J)), acarboxyl group, a C1-6 alkoxycarbonyl group (wherein the alkoxycarbonylgroup is optionally substituted by one to three groups, which may be thesame or different, selected from substituent group A^(J)), anaminocarbonyl group (wherein the aminocarbonyl group is optionallysubstituted by one or two groups, which may be the same or differentC1-6 alkyl groups each optionally substituted by one to three groups,which may be the same or different, selected from substituent groupA^(J)), or a cyano group, X represents —CH═, —C(—R⁷)═, or —N═, mrepresents an integer selected from 1 to 4, and the substituent groupsrepresent A^(B): a hydroxy group, a C1-6 alkyl group (wherein the alkylgroup is optionally substituted by one to three halogeno groups), a C1-6alkoxy group (wherein the alkoxy group is optionally substituted by oneto three halogeno groups), a halogeno group, an amino group, and a cyanogroup; A^(C): a C6-10 aryl group, a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur, and a halogeno group; A^(D):a hydroxy group, a C1-6 alkoxy group, an amino group, a halogeno group,and a cyano group; A^(E): a hydroxy group, a C1-6 alkoxy group, a C3-8cycloalkyl group, a C6-10 aryl group, a 3- to 10-membered heterocyclylgroup containing one to four heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur, an amino group(wherein the amino group is optionally substituted by one or two groups,which may be the same or different C1-6 alkyl groups), a halogeno group,and a cyano group; A^(F): a C1-6 alkoxy group, a C3-8 cycloalkyl group,a C6-10 aryl group, a 3- to 10-membered heterocyclyl group containingone to four heteroatoms, which may be the same or different, selectedfrom nitrogen, oxygen, and sulfur, a halogeno group, and a cyano group;A^(G): a hydroxy group, a C1-6 alkoxy group, an amino group (wherein theamino group is optionally substituted by one or two groups, which may bethe same or different C1-6 alkyl groups), a halogeno group, and a cyanogroup; A^(H): a hydroxy group, a C1-6 alkoxy group, a C3-8 cycloalkylgroup, a C6-10 aryl group, a 3- to 10-membered heterocyclyl groupcontaining one to four heteroatoms, which may be the same or different,selected from nitrogen, oxygen, and sulfur, a carboxyl group, a C1-6alkoxycarbonyl group, an aminocarbonyl group (wherein the aminocarbonylgroup is optionally substituted by one or two groups, which may be thesame or different C1-6 alkyl groups), an amino group (wherein the aminogroup is optionally substituted by one or two groups, which may be thesame or different C1-6 alkyl groups), a halogeno group, and a cyanogroup; and A^(J): a C1-6 alkoxy group, a C3-8 cycloalkyl group, a C6-10aryl group, a 3- to 10-membered heterocyclyl group containing one tofour heteroatoms, which may be the same or different, selected fromnitrogen, oxygen, and sulfur, a carboxyl group, a C1-6 alkoxycarbonylgroup, an aminocarbonyl group (wherein the aminocarbonyl group isoptionally substituted by one or two groups, which may be the same ordifferent C1-6 alkyl groups), a halogeno group, and a cyano group, or apharmacologically acceptable salt thereof.
 2. A compound represented byformula (Ia):

wherein R¹ represents a hydrogen atom, a C1-6 alkyl group (wherein thealkyl group is optionally substituted by one hydroxy group or C1-6alkoxy group), a C6-10 aryl group, or a 3- to 10-membered heterocyclylgroup containing one to four heteroatoms, which may be the same ordifferent, selected from nitrogen, oxygen, and sulfur, R² and R³ are thesame or different and each represent a hydrogen atom or a C1-6 alkylgroup (wherein the alkyl group is optionally substituted by one hydroxygroup), or the C1-6 alkyl groups of R² and R³ are optionally bonded toeach other to form a 3- to 6-membered saturated carbocyclic ring, eachsubstituent R⁷ may be the same or different and may represent a C1-6alkoxy group (wherein the alkoxy group is optionally substituted by oneto three halogeno groups) or a halogeno group, X represents —CH═,—C(—R⁷)═, or —N═, and m represents an integer of 1 or 2, or apharmacologically acceptable salt thereof.
 3. The compound according toclaim 2, wherein R¹ is hydrogen atom.
 4. The compound according to claim2, wherein R² and R³ are the same or different and each represent ahydrogen atom or the C1-6 alkyl groups of R² and R³ are optionallybonded to each other to form a 3- to 6-membered saturated carbocyclicring.
 5. The compound according to claim 2, wherein each substituent R⁷may be the same or different and may represent a methoxy group, ethoxygroup, trifluoromethoxy group, fluoro or chloro.
 6. A compound accordingto claim 1, wherein the pharmacologically acceptable salt is sodiumsalt.
 7. A compound according to claim 1, wherein the pharmacologicallyacceptable salt is potassium salt.
 8. A pharmaceutical compositioncomprising a compound according to claim 1 or a pharmacologicallyacceptable salt thereof, as an active ingredient, and apharmacologically acceptable carrier.
 9. A compound according to claim2, wherein the pharmacologically acceptable salt is sodium salt.
 10. Acompound according to claim 2, wherein the pharmacologically acceptablesalt is sodium salt.
 11. A compound according to claim 2, wherein thepharmacologically acceptable salt is potassium salt.